Isothiazole dioxides as CXC- and CC-chemokine receptor ligands

ABSTRACT

Disclosed are novel compounds of the formula: 
                         
and the pharmaceutically acceptable salts and solvates thereof. D and E are different groups wherein one is N and the other is CR 50 . Examples of groups comprising Substituent A include heteroaryl, aryl, heterocycloalkyl, cycloalkyl, aryl, alkynyl, alkenyl, aminoalkyl, alkyl or amino. Examples of groups comprising Substituent B include aryl and heteroaryl. Also disclosed is a method of treating a chemokine mediated diseases, such as, cancer, angiogenisis, angiogenic ocular diseases, pulmonary diseases, multiple sclerosis, rheumatoid arthritis, osteoarthritis, stroke and cardiac reperfusion injury, pain (e.g., acute pain, acute and chronic inflammatory pain, and neuropathic pain) using a compound of formula IA.

REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/531693 filed Dec. 22, 2003, the disclosure of which is incorporatedherein by reference thereto.

FIELD OF THE INVENTION

The present invention relates to novel substituted isothiazole dioxidecompounds, pharmaceutical compositions containing the compounds, and theuse of the compounds and formulations in treating CXC andCC-chemokine-mediated diseases.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract macrophages, T-cells, eosinophils, basophils,neutrophils and endothelial cells to sites of inflammation and tumorgrowth. There are two main classes of chemokines, the CXC-chemokines andthe CC-chemokines. The class depends on whether the first two cysteinesare separated by a single amino acid (CXC-chemokines) or are adjacent(CC-chemokines). The CXC-chemokines include, but are not limited to,interleukin-8 (IL-8), neutrophil-activating protein-1 (NAP-1),neutrophil-activating protein-2 (NAP-2), GROα, GROβ, GROγ, ENA-78,GCP-2, IP-10, MIG and PF4. CC chemokines include, but are not limitedto, RANTES, MIP-1α, MIP-2β, monocyte chemotactic protein-1 (MCP-1),MCP-2, MCP-3, CCL19, CCL21 and eotaxin. Individual members of thechemokine families are known to be bound by at least one chemokinereceptor, with CXC-chemokines generally bound by members of the CXCRclass of receptors, and CC-chemokines by members of the CCR class ofreceptors. For example, IL-8 is bound by the CXCR-1 and CXCR-2receptors.

Since CXC-chemokines promote the accumulation and activation ofneutrophils, these chemokines have been implicated in a wide range ofacute and chronic inflammatory disorders including psoriasis andrheumatoid arthritis. Baggiolini et al., FEBS Lett. 307, 97 (1992);Miller et al., Crit. Rev. Immunol. 12,17 (1992); Oppenheim et al., Annu.Fev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87, 463(1991); Miller et al., Am. Rev. Respir. Dis. 146, 427 (1992); Donnely etal., Lancet 341, 643 (1993).

ELRCXC chemokines including IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78(Strieter et al. 1995 JBC 270 p. 27348-57) have also been implicated inthe induction of tumor angiogenesis (new blood vessel growth). All ofthese chemokines are believed to exert their actions by binding to the 7transmembrane G-protein coupled receptor CXCR2 (also known as IL-8RB),while IL-8 also binds CXCR1 (also known as IL-8RA). Thus, theirangiogenic activity is due to their binding to and activation of CXCR2,and possible CXCR1 for IL-8, expressed on the surface of vascularendothelial cells (ECs) in surrounding vessels.

Many different types of tumors have been shown to produce ELRCXCchemokines and their production has been correlated with a moreaggressive phenotype (Inoue et al. 2000 Clin Cancer Res 6 p. 2104-2119)and poor prognosis (Yoneda et. al. 1998 J Nat Cancer Inst 90 p.447-454). Chemokines are potent chemotactic factors and the ELRCXCchemokines have been shown to induce EC chemotaxis. Thus, thesechemokines probably induce chemotaxis of endothelial cells toward theirsite of production in the tumor. This may be a critical step in theinduction of angiogenesis by the tumor. Inhibitors of CXCR2 or dualinhibitors of CXCR2 and CXCR1 will inhibit the angiogenic activity ofthe ELRCXC chemokines and therefore block the growth of the tumor. Thisanti-tumor activity has been demonstrated for antibodies to IL-8(Arenberg et al. 1996 J Clin Invest 97 p. 2792-2802), ENA-78 (Arenberget al. 1998 J Clin Invest 102 p. 465-72), and GROα (Haghnegahdar et al.J. Leukoc Biology 2000 67 p. 53-62).

Many tumor cells have also been shown to express CXCR2 and thus tumorcells may also stimulate their own growth when they secrete ELRCXCchemokines. Thus, along with decreasing angiogenesis, inhibitors ofCXCR2 may directly inhibit the growth of tumor cells.

Hence, the CXC-chemokine receptors represent promising targets for thedevelopment of novel anti-inflammatory and anti-tumor agents.

There remains a need for compounds that are capable of modulatingactivity at CXC-chemokine receptors. For example, conditions associatedwith an increase in IL-8 production (which is responsible for chemotaxisof neutrophil and T-cell subsets into the inflammatory site and growthof tumors) would benefit by compounds that are inhibitors of IL-8receptor binding.

SUMMARY OF THE INVENTION

This invention provides novel compounds of formula IA:

and the pharmaceutically acceptable salts (e.g., sodium or calcium)thereof, wherein A, B, D and E are defined below.

This invention also provides a method of treating a chemokine mediateddisease or condition in a patient in need of such treatment comprisingadministering to said patient an effective amount of at least onecompound (usually 1) of formula IA, or a pharmaceutically acceptablesalt thereof.

This invention also provides a method of treating a CXCR1 and/or CXCR2mediated disease or condition in a patient in need of such treatmentcomprising administering to said patient an effective amount of at leastone compound (usually 1) of formula IA, or a pharmaceutically acceptablesalt thereof.

This invention also provides a method of treating a CCR7 mediateddisease or condition in a patient in need of such treatment comprisingadministering to said patient an effective amount of at least onecompound (usually 1) of formula IA, or a pharmaceutically acceptablesalt thereof.

This invention also provides a method of treating cancer in a patient inneed of such treatment comprising administering to said patient aneffective amount of at least one (usually 1) compound of formula IA, ora pharmaceutically acceptable salt thereof.

This invention also provides a method of treating Kaposi's sarcoma,melanoma, gastric carcinoma, and non-small cell carcinoma in a patientin need of such treatment comprising administering to said patient aneffective amount of at least one (usually 1) compound of formula IA, ora pharmaceutically acceptable salt thereof.

This invention also provides a method of treating melanoma, gastriccarcinoma, and non-small cell carcinoma in a patient in need of suchtreatment comprising administering to said patient an effective amountof at least one (usually 1) compound of formula IA, or apharmaceutically acceptable salt thereof.

This invention also provides a method of treating cancer in a patient inneed of such treatment comprising administering to said patient aneffective amount of at least one (usually 1) compound of formula IA, ora pharmaceutically acceptable salt thereof, in combination with at leastone anticancer agent selected from the group consisting of: (a)microtubule affecting agents, (b) antineoplastic agents, (c)anti-angiogenesis agents, or (d) VEGF receptor kinase inhibitors, (e)antibodies against the VEGF receptor, (f) interferon, and g) radiation.The compound of formula IA can be administered concurrently orsequentially with the anticancer agent.

This invention also provides a method of treating cancer in a patient inneed of such treatment comprising administering to said patient at leastone (usually 1) compound of formula IA, or a pharmaceutically acceptablesalt thereof, in combination with at least one (usually 1)antineoplastic agent selected from the group consisting of: gemcitabine,paclitaxel (Taxol®)), 5-Fluorourcil (5-FU), cyclophosphamide (Cytoxan®),temozolomide, and Vincristine.

This invention also provides a method of treating cancer in a patient inneed of such treatment comprising administering to said patient aneffective amount of at least one (usually 1) compound of formula IA, ora pharmaceutically acceptable salt thereof, concurrently or sequentiallywith microtubule affecting agent, e.g., paclitaxel.

This invention also provides a method treating cancer in a patient inneed of such treatment comprising administering to said patient atherapeutically effective amount of: (a) at least one (usually 1)compound of formula IA, or a pharmaceutically acceptable salt thereof,concurrently or sequentially with (b) at least one (usually 1) agentselected from the group consisting of: (1) antineoplastic agents, (2)microtubule affecting agents, and (3) anti-angiogenesis agents.

This invention also provides a method of inhibiting angiogenesis in apatient in need of such treatment comprising administering to saidpatient an effective amount of at least one (usually 1) compound offormula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating angiogenic oculardisease (e.g., ocular inflammation, retinopathy of prematurity, diabeticretinopathy, macular degeneration with the wet type preferred andcorneal neovascularization) in a patient in need of such treatmentcomprising administering to said patient an effective amount of at leastone (usually 1) compound of formula IA, or a pharmaceutically acceptablesalt thereof.

This invention also provides a method of treating a chemokine mediated(e.g., CXCR1 and/or CXCR2, or CCR7) disease or condition selected fromthe group consisting of: pain (e.g., acute pain, acute inflammatorypain, chronic inflammatory pain, and neuropathic pain), acuteinflammation, chronic inflammation, rheumatoid arthritis, psoriasis,atopic dermatitis, asthma, COPD, adult respiratory disease, arthritis,inflammatory bowel disease, Crohn's disease, ulcerative colitis, septicshock, endotoxic shock, gram negative sepsis, toxic shock syndrome,stroke, ischemia reperfusion injury, renal reperfusion injury,glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. hostreaction (i.e., graft vs. host disease), allograft rejections (e.g.,acute allograft rejection, and chronic allograft rejection), malaria,acute respiratory distress syndrome, delayed type hypersensitivityreaction, atherosclerosis, cerebral ischemia, cardiac ischemia,osteoarthritis, multiple sclerosis, restinosis, angiogenesis,osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitisviruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposi'ssarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritis,multi-organ dysfunction, trauma, strains, sprains, contusions, psoriaticarthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury,CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitialpneumonitis, hypersensitivity, crystal induced arthritis, acutepancreatitis, chronic pancreatitis, acute alcoholic hepatitis,necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease,ocular inflammation, retinopathy of prematurity, diabetic retinopathy,macular degeneration with the wet type preferred, cornealneovascularization, polymyositis, vasculitis, acne, gastric ulcers,duodenal ulcers, celiac disease, esophagitis, glossitis, airflowobstruction, airway hyperresponsiveness (i.e., airway hyperreactivity),bronchiectasis, bronchiolitis, bronchiolitis obliterans (i.e.,bronchiolitis obliterans syndrome), chronic bronchitis, cor pulmonae,dyspnea, emphysema, hypercapnea, hyperinflation, hypoxemia,hyperoxia-induced inflammations, hypoxia, surgical lung volumereduction, pulmonary fibrosis, pulmonary hypertension, right ventricularhypertrophy, peritonitis associated with continuous ambulatoryperitoneal dialysis (CAPD), granulocytic ehrlichiosis, sarcoidosis,small airway disease, ventilation-perfusion mismatching, wheeze, colds,gout, alcoholic liver disease, lupus, burn therapy (i.e., the treatmentof burns), periodontitis, cancer, transplant reperfusion injury, earlytransplantation rejection (e.g., acute allograft rejection), airwayhyperreactivity, allergic contact dermatitis, allergic rhinitis,alopecia areata, antiphospholipid syndromes, aplastic anemia, autoimmunedeafness (including, for example, Meniere's disease), autoimmunehemolytic syndromes, autoimmune hepatitis, autoimmune neuropathy,autoimmune ovarian failure, autoimmune orchitis, autoimmunethrombocytopenia, bullous pemphigoid, chronic allograft vasculopathy,chronic inflammatory demyelinating polyneuropathy, cirrhosis, corpneumoniae, cryoglobulinemia, dermatomyositis, diabetes, drug-inducedautoimmunity, epidermolysis bullosa acquisita, endometriosis, fibroticdiseases, gastritis, Goodpasture's syndrome, Graves' disease,GuIlain-Barre disease, Hashimoto's thyroiditis, hepatitis-associatedautoimmunity, HIV-related autoimmune syndromes and hematologicdisorders, hypophytis, idiopathic thrombocytic pupura, interstitialcystitis, juvenile arthritis, Langerhans' cell histiocytitis, lichenplanus, metal-induced autoimmunity, myasthenia gravis, myelodysplasticsyndromes, myocarditis (including viral myocarditis), myositis,Neuropathies (including, for example, IgA neuropathy, membranousneuropathy and idiopathic neuropathy), nephritic syndrome, opticneuritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia,pemphigus, polymyalgia, post-infectious autoimmunity, primary biliarycirrhosis, reactive arthritis, ankylosing spondylitis, Raynaud'sphenomenon, Reiter's syndrome, reperfusion injury, scleritis,scleroderma, secondary hematologic manifestation of autoimmune diseases(such as, for example, anemias), silicone implant associated autoimmunedisease, Sjogren's syndrome, systemic lupus erythematosus,thrombocytopenia, transverse myelitis, tubulointerstitial nephritis,uveitis, vasculitis syndromes (such as, for example, giant cellarteritis, Behcet's disease and Wegener's granulomatosis), and Vitiligoin a patient in need of such treatment comprising administering to saidpatient an effective amount of at least one compound (usually 1) offormula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating a CXCR1 and/or a CXCR2mediated disease or condition selected from the group consisting of:pain (e.g., acute pain, acute inflammatory pain, chronic inflammatorypain, and neuropathic pain), acute inflammation, chronic inflammation,rheumatoid arthritis, psoriasis, atopic dermatitis, asthma, COPD, adultrespiratory disease, arthritis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, stroke, ischemia reperfusioninjury, renal reperfusion injury, glomerulonephritis, thrombosis,Alzheimer's disease, graft vs. host reaction (i.e., graft vs. hostdisease), allograft rejections (e.g., acute allograft rejection, andchronic allograft rejection), malaria, acute respiratory distresssyndrome, delayed type hypersensitivity reaction, atherosclerosis,cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis,restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses,herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associatedvirus (i.e., Kaposi's sarcoma), meningitis, cystic fibrosis, pre-termlabor, cough, pruritis, multi-organ dysfunction, trauma, strains,sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNSvasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage,post surgical trauma, interstitial pneumonitis, hypersensitivity,crystal induced arthritis, acute pancreatitis, chronic pancreatitis,acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis,angiogenic ocular disease, ocular inflammation, retinopathy ofprematurity, diabetic retinopathy, macular degeneration with the wettype preferred, corneal neovascularization, polymyositis, vasculitis,acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis,glossitis, airflow obstruction, airway hyperresponsiveness (i.e., airwayhyperreactivity), bronchiectasis, bronchiolitis, bronchiolitisobliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema,hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations,hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertrophy, peritonitis associated withcontinuous ambulatory peritoneal dialysis (CAPD), granulocyticehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusionmismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burntherapy (i.e., the treatment of burns), periodontitis, cancer,transplant reperfusion injury, early transplantation rejection (e.g.,acute allograft rejection) in a patient in need of such treatmentcomprising administering to said patient an effective amount of at leastone compound (usually 1) of formula IA, or a pharmaceutically acceptablesalt thereof.

This invention also provides a method of treating a CCR7 mediateddisease or condition selected from the group consisting of: pain (e.g.,acute pain, acute inflammatory pain, chronic inflammatory pain, andneuropathic pain), acute inflammation, chronic inflammation, acuteallograft rejection, acute respiratory distress syndrome, adultrespiratory disease, airway hyperreactivity, allergic contactdermatitis, allergic rhinitis, alopecia areata, alzheimer's disease,angiogenic ocular disease, antiphospholipid syndromes, aplastic anemia,asthma, atherosclerosis, atopic dermatitis, autoimmune deafness(including, for example, Meniere's disease), autoimmune hemolyticsyndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmuneovarian failure, autoimmune orchitis, autoimmune thrombocytopenia,bronchiolitis, bronchiolitis obliterans syndrome, bullous pemphigoid,burn therapy (i.e., the treatment of burns), cancer, cerebral ischemia,cardiac ischemia, chronic allograft rejection, chronic allograftvasculopathy, chronic bronchitis, chronic inflammatory demyelinatingpolyneuropathy, chronic sinusitis, cirrhosis, CNS vasculitis, COPD, Corpneumoniae, Crohn's disease, cryoglobulinemia, crystal-inducedarthritis, delayed-type hypersensitivity reactions, dermatomyositis,diabetes, diabetic retinopathy, drug-induced autoimmunity, dyspnea,emphysema, epidermolysis bullosa acquisita, endometriosis, fibroticdiseases, gastritis, glomerulonephritis, Goodpasture's syndrome, graftvs host disease, Graves' disease, Gullain-Barre disease, Hashimoto'sthyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmunesyndromes and hematologic disorders, hyperoxia-induced inflammation,hypercapnea, hyperinflation, hypophytis, hypoxia, idiopathicthrombocytic pupura, inflammatory bowel diseases, interstitial cystitis,interstitial pneumonitis, juvenile arthritis, Langerhans' cellhistiocytitis, lichen planus, metal-induced autoimmunity, multiplesclerosis, myasthenia gravis, myelodysplastic syndromes, myocarditisincluding viral myocarditis, myositis, neuropathies (including, forexample, IgA neuropathy, membranous neuropathy and idiopathicneuropathy), nephritic syndrome, ocular inflammation, optic neuritis,osteoarthritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia,pemphigus, polymyalgia, polymyositis, post-infectious autoimmunity,pulmonary fibrosis, primary biliary cirrhosis, psoriasis, pruritis,rheumatoid arthritis, reactive arthritis, ankylosing spondylitis,psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome,reperfusion injury, restenosis, sarcoidosis, scleritis, scleroderma,secondary hematologic manifestation of autoimmune diseases (such as, forexample, anemias), silicone implant associated autoimmune disease,Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia,thrombosis, transverse myelitis, tubulointerstitial nephritis,ulcerative colitis, uveitis, vasculitis and vasculitis syndromes (suchas, for example, giant cell arteritis, Behcet's disease and Wegener'sgranulomatosis), and vitiligo in a patient in need of such treatmentcomprising administering to said patient an effective amount of at leastone compound (usually 1) of formula IA, or a pharmaceutically acceptablesalt thereof.

This invention also provides a method of treating a chemokine (e.g., aCXC, or a CC chemokine) mediated disease or condition in a patient inneed of such treatment comprising administering to said patient at leastone (usually 1) compound of formula IA, or a pharmaceutically acceptablesalt thereof, in combination with at least one (usually 1) othermedicament (e.g., a drug, agent or therapeutic) useful for the treatmentof chemokine mediated diseases.

This invention also provides a method of treating a chemokine mediateddisease or condition in a patient in need of such treatment comprisingadministering to said patient at least one (usually 1) compound offormula IA, or a pharmaceutically acceptable salt thereof, incombination with at least one (usually 1) other medicament (e.g., adrug, agent or therapeutic) selected from the group consisting of:

-   -   a) disease modifying antirheumatic drugs;    -   b) nonsteroidal anitinflammatory drugs;    -   c) COX-2 selective inhibitors;    -   d) COX-1 inhibitors;    -   e) immunosuppressives;    -   f) steroids;    -   g) biological response modifiers; and    -   h) other anti-inflammatory agents or therapeutics useful for the        treatment of chemokine mediated diseases.

This invention also provides a method of treating a pulmonary disease(e.g., COPD, asthma or cystic fibrosis) in a patient in need of suchtreatment comprising administering to said patient a therapeuticallyeffective amount of at least one compound (usually 1) of formula IA, ora pharmaceutically acceptable salt thereof, in combination with at leastone (usually 1) compound selected from the group consisting of:glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists,muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotrieneantagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastaseinhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase Dinhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamineagonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-bagonists, nociceptin agonists, expectorants, mucolytic agents,decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesionmolecule inhibitors, and growth hormones.

This invention also provides a method of treating multiple sclerosis ina patient in need of such treatment comprising administering to saidpatient, a therapeutically effective amount of at least one (usually 1)compound of formula IA, or a pharmaceutically acceptable salt thereof,in combination with at least one compound selected from the groupconsisting of glatiramer acetate, glucocorticoids, methotrexate,azothioprine, mitoxantrone, chemokine inhibitors, and CB2-selectiveagents.

This invention also provides a method of treating multiple sclerosis ina patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually 1)compound of formula IA, or a pharmaceutically acceptable salt thereof,in combination with at least one compound selected from the groupconsisting of: methotrexate, cyclosporin, leflunimide, sulfasalazine,β-methasone, β-interferon, glatiramer acetate, and prednisone.

This invention also provides a method of treating rheumatoid arthritisin a patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating rheumatoid arthritisin a patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually 1)compound of formula IA, or a pharmaceutically acceptable salt thereof,in combination with at least one compound selected from the groupconsisting of COX-2 inhibitors, COX inhibitors, immunosuppressives(e.g., methotrexate, cyclosporin, leflunimide and sulfasalazine),steroids (e.g., betamethasone, cortisone and dexamethasone), PDE IVinhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids,chemokine inhibitors, CB2-selective inhibitors, and other classes ofcompounds indicated for the treatment of rheumatoid arthritis.

This invention also provides a method of treating stroke and cardiacreperfusion injury in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of atleast one compound (usually 1) of formula IA, or a pharmaceuticallyacceptable salt thereof, in combination with at least one compoundselected from the group consisting of thrombolitics (e.g., tenecteplase,TPA, alteplase), antiplatelet agents (e.g., gpIIb/IIIa), antagonists(e.g., abciximab and eftiifbatide), anticoagulants (e.g., heparin), andother compounds indicated for the treatment of rheumatoid arthritis.

This invention also provides a method of treating stroke and cardiacreperfusion injury in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of atleast one (usually 1) compound of formula IA, or a pharmaceuticallyacceptable salt thereof, in combination with at least one compoundselected from the group consisting of tenecteplase, TPA, alteplase,abciximab, eftiifbatide, and heparin.

This invention also provides a method of treating psoriasis in a patientin need of such treatment comprising administering to said patient athereapeutically effective amount of at least one (usually 1) compoundof formula IA, or a pharmaceutically acceptable salt thereof, incombination with at least one compound selected from the groupconsisting of immunosuppressives (e.g., methotrexate, cyclosporin,leflunimide and sulfasalazine), steroids (e.g., β-methasone) andanti-TNF-α compounds (e.g., etonercept and infliximab).

This invention also provides a method of treating COPD in a patient inneed of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundof formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating arthritis in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundof formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating osteoarthritis in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating pain in a patient inneed of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundof formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating pain in a patient inneed of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundof formula IA, or a pharmaceutically acceptable salt thereof, andadministering a therapeutically effective amount of at least onemedicament selected from the group consisting of: NSAIDs, COXIBinhibitors, anti-depressants, and anti-convulsants.

This invention also provides a method of treating acute pain in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a method of treating acute inflammatorypain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of formula IA, or a pharmaceutically acceptable saltthereof.

This invention also provides a method of treating chronic inflammatorypain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of formula IA, or a pharmaceutically acceptable saltthereof.

This invention also provides a method of treating neropathic pain in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound of formula IA, or a pharmaceutically acceptable salt thereof.

This invention also provides a pharmaceutical composition comprising atleast one (e.g., 1-3, usually 1) compound of formula IA, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

This invention also provides a pharmaceutical composition comprising atleast one (e.g., 1-3, usually 1) compound of formula IA, or apharmaceutically acceptable salt thereof, and at least one (e.g., 1-3,usually 1) other agent, medicament, antibody and/or inhibitor disclosedabove, and a pharmaceutically acceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

When any variable occurs more than one time in any moiety, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Also, combinations of substituents and/or variablesare permissible only if such combinations result in stable compounds.

Unless indicated otherwise, the following definitions apply throughoutthe present specification and claims. These definitions apply regardlessof whether a term is used by itself or in combination with other terms.For example, the definition of “alkyl” also applies to the “alkyl”portion of “alkoxy”.

“An effective amount” means a therapeutically acceptable amount (i.e.,that amount which provides the desired therapeutic effective).

“At least one” means one or more (e.g., 1-3, 1-2, or 1).

“Bu” represents butyl.

“Bn” represents benzyl.

“Composition” includes a product comprising the specified ingredients inthe specified amounts, as well as any product that results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

“Et” represents ethyl.

“In combination with” as used to describe the administration of acompound of formula IA with other medicaments in the methods oftreatment of this invention, means that the compounds of formula IA andthe other medicaments are administered sequentially or concurrently inseparate dosage forms, or are administered concurrently in the samedosage form.

“Mammal” includes a human being, and preferably means a human being.

“Patient” includes both human and other mammals, preferably human.

“Ph”, as used in the structures herein, represents phenyl.

“Pr” represents propyl.

“Prodrug” represents compounds that are rapidly transformed in vivo tothe parent compound of the above formula, for example, by hydrolysis inblood. A thorough discussion is provided in T. Higuchi and V. Stella,Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. SymposiumSeries, and in Edward B. Roche, ed., Bioreversible Carriers in DrugDesign, American Pharmaceutical Association and Pergamon Press, 1987,both of which are incorporated herein by reference.

“Alkyl” means a straight or branched saturated hydrocarbon chain having1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1to 6 carbon atoms.

“Alkoxy” means an alkyl-O— group wherein alkyl is as defined above.Non-limiting examples of alkoxy groups include: methoxy, ethoxy,n-propoxy, iso-propoxy and n-butoxy. The bond to the parent moiety isthrough the ether oxygen.

“Alkenyl” means a straight or branched aliphatic hydrocarbon grouphaving at least one carbon-carbon double bond, and 2 to 20 carbon atoms,preferably 2 to 12 carbon atoms, and more preferably 2 to 6 carbonatoms. Non-limiting examples of alkenyl groups include: ethenyl,propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl anddecenyl.

“Alkynyl” means a straight or branched aliphatic hydrocarbon grouphaving at least one carbon-carbon triple bond, and 2 to 15 carbon atoms,preferably 2 to 12 carbon atoms, and more preferably 2 to 4 carbonatoms. Non-limiting examples of alkynyl groups include ethynyl,propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring system, whereinat least one ring is aromatic, comprising about 6 to about 14 carbonatoms, and preferably about 6 to about 10 carbon atoms. Non-limitingexamples of suitable aryl groups include: phenyl, naphthyl, indenyl,tetrahydronaphthyl, indanyl, anthracenyl, and fluorenyl.

“Arylalkyl” means an aryl group, as defined above, bound to an alkylgroup, as defined above, wherein the alkyl group is bound to the parentmoiety. Non-limiting examples of suitable arylalkyl groups includebenzyl, phenethyl and naphthleneylmethyl.

“Bn” represents benzyl.

“Cycloalkyl” means saturated carbocyclic rings having 3 to 10 (e.g., 3to 7) carbon atoms, preferably 5 to 10 carbon atoms, and more preferably5 to 7 carbon atoms, and having one to three rings. Non-limitingexamples of cycloalkyl groups include: cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, norbornyl, and adamantyl.

“Cycloalkylalkyl” means a cycloalkyl group bound to the parent moietythrough an alkyl group. Non-limiting examples include: cyclopropylmethyland cyclohexylmethyl.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising 3 to 10 carbon atoms, and preferably 5 to 10 carbon atoms,and having at least one carbon-carbon double bond. Preferredcycloalkenyl rings have 5 to 7 carbon atoms. Non-limiting examples ofcycloalkyl groups include cyclopentenyl, cyclohexenyl, cycloheptenyl,and norbornenyl.

“Et” represents ethyl.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Halogen” means fluorine, chlorine, bromine, or iodine. Preferred arefluorine, chlorine or bromine, and more preferred are fluorine andchlorine.

“Haloalkyl” means an alkyl group as defined above wherein one or morehydrogen atoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” or “heterocyclic” or “heterocycloalkyl” means anon-aromatic saturated monocyclic or multicyclic ring system (i.e., asaturated carbocyclic ring or ring system) comprising 3 to 10 ring atoms(e.g., 3 to 7 ring atoms), preferably 5 to 10 ring atoms, in which oneor more of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls have 5 to 6 ring atoms. The prefix aza, oxa orthia before the heterocyclyl root name means that at least a nitrogen,oxygen or sulfur atom, respectively, is present as a ring atom. Thenitrogen or sulfur atom of the heterocyclyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limitingexamples of monocyclic heterocyclyl rings include: piperidyl,pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl,1,3-dioxolanyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl,and tetrahydrothiopyranyl.

The term heterocyclic acidic functional group is intended to includegroups such as, pyrrole, imidazole, triazole, tetrazole, and the like.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in whichone or more of the ring atoms is an element other than carbon, forexample nitrogen, oxygen or sulfur, alone or in combination. Preferredheteroaryls contain 5 to 6 ring atoms. The prefix aza, oxa or thiabefore the heteroaryl root name means that at least a nitrogen, oxygenor sulfur atom respectively, is present as a ring atom. A nitrogen atomof a heteroaryl can be optionally oxidized to the corresponding N-oxide.Non-limiting examples of heteroaryls include: pyridyl, pyrazinyl,furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl,thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, and benzothiazolyl.

“Heteroarylalkyl” means a heteroaryl group, as defined above, bound toan alkyl group, as defined above, where the bond to the parent moiety isthrough the alkyl group.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules; This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding; In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid; “Solvate” encompasses bothsolution-phase and isolatable solvates; Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like;“Hydrate” is a solvate wherein the solvent molecule is H₂O.

The term “pharmaceutical composition” is also intended to encompass boththe bulk composition and individual dosage units comprised of more thanone (e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the aforesaid “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

N-oxides can form on a tertiary nitrogen present in an R substituent, oron ═N— in a heteroaryl ring substituent and are included in thecompounds of formula IA.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom. For example:

The compounds of this invention are represented by formula IA:

and the pharmaceutically acceptable salts (e.g., sodium or calcium salt)thereof, wherein:

D and E are independently selected from the group consisting of: N andCR⁵⁰, provided that D and E are not the same;

R⁵⁰ is selected from the group consisting of: H, —C(O)R¹³, —C(O)OR¹³,—C(O)NR¹³R¹⁴, —S(O)₂NR¹³R¹⁴, —CF₃, —CN, —NO₂, —NR¹³R¹⁴, R¹³ and halo(e.g., Cl and Br), and R⁵⁰ is preferably H;

A is selected from the group consisting of:

wherein the above rings of said A groups are substituted with 1 to 6substituents each independently selected from the group consisting of:R⁹ groups;

wherein one or both of the above rings of said A groups are substitutedwith 1 to 6 substituents each independently selected from the groupconsisting of: R⁹ groups;

wherein the above phenyl rings of said A groups are substituted with 1to 3 substituents each independently selected from the group consistingof: R⁹ groups; and

B is selected from the group consisting of

n is 0 to 6;

p is 1 to 5;

X is O, NR¹⁸, or S;

Z is 1 to 3;

R² is selected from the group consisting of: hydrogen, OH, —C(O)OH, —SH,—SO₂NR¹³R¹⁴, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³ , —NR ¹³R¹⁴,—C(O)NR¹³R¹⁴, —C(O)NHOR¹³, —C(O)NR¹³OH, —S(O₂)OH, —OC(O)R¹³, anunsubstituted heterocyclic acidic functional group, and a substitutedheterocyclic acidic functional group; wherein there are 1 to 6substituents on said substituted heterocyclic acidic functional groupeach substituent being independently selected from the group consistingof: R⁹ groups;

each R³ and R⁴ is independently selected from the group consisting of:hydrogen, cyano, halogen, alkyl, cycloalkyl substituted with 1 to 4alkyl groups (preferably C₁ to C₆ alkyl groups) wherein each alkyl groupis independently selected, unsubstituted cycloalkyl, alkoxy, —OH, —CF₃,—OCF₃, —NO₂, —C(O)R³, —C(O)OR¹³, —C(O)NHR¹⁷, —C(O)NR¹³R¹⁴,—SO_((t))NR¹³R¹⁴, —SO_((t))R¹³, —C(O)NR¹³OR¹⁴, unsubstituted orsubstituted aryl, unsubstituted or substituted heteroaryl,

wherein there are 1 to 6 substituents on said substituted aryl group andeach substituent is independently selected from the group consisting of:R⁹ groups; and wherein there are 1 to 6 substituents on said substitutedheteroaryl group and each substituent is independently selected from thegroup consisting of: R⁹ groups; or

R³ is and R⁴ taken together with the carbons atoms to which they arebonded to in the phenyl B substituent

form a fused ring of the formula:

(preferably Z¹) wherein Z¹ or Z² is an unsubstituted or substitutedsaturated heterocyclic ring (preferably a 4 to 7 membered heterocyclicring), said ring Z¹ or Z² optionally containing one additionalheteroatom selected from the group consisting of: O, S and NR¹⁸; whereinthere are 1 to 3 substituents on said ring Z¹ or Z², and eachsubstituent is independently selected from the group consisting of:alkyl, aryl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl,fluoroalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl,amino, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵provided that R¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and aheterocycloalkenyl group (i.e., a heterocyclic group that has at leastone, and preferably one, double bond in a ring, e.g.,

examples of the fused ring moiety include, but are not limited to:

each R⁵ and R⁶ are the same or different and are independently selectedfrom the group consisting of hydrogen, halogen, alkyl, alkoxy, —CF₃,—OCF₃, —NO₂, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —SO_((t))NR¹³R¹⁴,—C(O)NR¹³OR¹⁴, cyano, unsubstituted or substituted aryl, andunsubstituted or substituted heteroaryl group; wherein there are 1 to 6substituents on said substituted aryl group and each substituent isindependently selected from the group consisting of: R⁹ groups; andwherein there are 1 to 6 substituents on said substituted heteroarylgroup and each substituent is independently selected from the groupconsisting of: R⁹ groups;

each R⁷ and R⁸ is independently selected from the group consisting of:H, unsubstituted or substituted alkyl, unsubstituted or substitutedaryl, unsubstituted or substituted heteroaryl, unsubstituted orsubstituted arylalkyl, unsubstituted or substituted heteroarylalkyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedcycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴, alkynyl, alkenyl, andcycloalkenyl; and wherein there are one or more (e.g., 1 to 6)substituents on said substituted R⁷ and R⁸ groups, wherein eachsubstitutent is independently selected from the group consisting of:

-   -   a) halogen,    -   b) —CF₃,    -   c) —COR¹³,    -   d) —OR¹³,    -   e) —NR¹³R¹⁴ ,    -   f) —NO₂,    -   g) —CN,    -   h) —SO₂OR¹³,    -   i) —Si(alkyl)₃, wherein each alkyl is independently selected,    -   j) —Si(aryl)₃, wherein each alkyl is independently selected,    -   k) —(R¹³)₂R¹⁴Si, wherein each R¹³ is independently selected,    -   l) —CO₂R¹³,    -   m) —C(O)NR¹³R¹⁴,    -   n) —SO₂NR¹³R¹⁴,    -   o) —SO₂R¹³,    -   p) —OC(O)R¹³,    -   q) —OC(O)NR¹³R¹⁴,    -   r) —NR¹³C(O)R¹⁴, and    -   s) —NR¹³CO₂R¹⁴;        (fluoroalkyl is one non-limiting example of an alkyl group that        is substituted with halogen);

R^(8a) is selected from the group consisting of: hydrogen, alkyl,cycloalkyl and cycloalkylalkyl;

each R⁹ is independently selected from the group consisting of:

-   -   a) —R¹³,    -   b) halogen,    -   c) —CF₃,    -   d) —COR¹³,    -   e) —OR¹³,    -   f) —NR¹³R¹⁴,    -   g) —NO₂,    -   h) —CN,    -   i) —SO₂R¹³,    -   j) —SO₂NR¹³R¹⁴,    -   k) —NR¹³CR¹⁴,    -   l) —CONR¹³R¹⁴,    -   m) —NR¹³CO₂R¹⁴,    -   n) —CO₂R¹³,    -   o)

-   -   p) alkyl substituted with one or more (e.g., one) —OH groups        (e.g., —(CH₂)_(q)OH, wherein q is 1-6, usually 1 to 2, and        preferably 1),    -   q) alkyl substituted with one or more (e.g., one) —NR¹³R¹⁴ group        (e.g., —(CH₂)_(q)NR¹³R¹⁴, wherein q is 14-6, usually 1 to 2, and        preferably 1), and    -   r) —N(R¹³)SO₂R¹⁴ (e.g., R¹³ is H and R¹⁴ is alkyl, such as        methyl);

each R¹⁰ and R¹¹ is independently selected from the group consisting ofR¹³, (e.g., hydrogen and alkyl (e.g., C₁ to C₆ alkyl, such as methyl)),halogen, —CF₃, —OCF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —OH, —C(O)OR¹³, —SH,—SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³ and cyano;

R¹² is selected from the group consisting of: hydrogen, —C(O)OR¹³,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted cycloalkyl, unsubstituted or substituted alkyl,unsubstituted or substituted cycloalkylalkyl, and unsubstituted orsubstituted heteroarylalkyl group; wherein there are 1 to 6 substituentson the substituted R¹² groups and each substituent is independentlyselected from the group consisting of: R⁹ groups;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, unsubstituted or substituted alkyl, unsubstituted or substitutedcyanoalkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl, unsubstituted or substituted arylalkyl,unsubstituted or substituted heteroarylalkyl, unsubstituted orsubstituted cycloalkyl, unsubstituted or substituted cyanocycloalkyl,unsubstituted or substituted cycloalkylalkyl, unsubstituted orsubstituted heterocyclic, unsubstituted or substituted fluoroalkyl, andunsubstituted or substituted heterocycloalkylalkyl (wherein“heterocyloalkyl” means heterocyclic); wherein there are 1 to 6substituents on said substituted R¹³ and R¹⁴ groups and each substituentis independently selected from the group consisting of: alkyl, —CF₃,—OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, —N(R⁴⁰)₂, —C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, halogen, —NHC(O)NR¹⁵R¹⁶, and —SO₂R¹⁵provided that R¹⁵ is not H; and provided that for the substitutedcyanoalkyl and the substituted cyanocycloalkyl moieties the carbon atomto which the cyano (CN) group is bound to does not also have bound tosaid carbon atom a substituent selected from the group consisting of:—OH, alkoxy, —N(R⁴⁰)₂, halogen and —NHC(O)NR¹⁵R¹⁶; or

R¹³ and R¹⁴ taken together with the nitrogen they are attached to in thegroups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form an unsubstituted or substitutedsaturated heterocyclic ring (preferably a 3 to 7 membered heterocyclicring), said ring optionally containing one additional heteroatomselected from the group consisting of: O, S and NR¹⁸; wherein there are1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., there is 1 to 3 substituents on the ring formed when the R¹³ andR¹⁴ groups are taken together with the nitrogen to which they are bound)and each substituent is independently selected from the group consistingof: CN, alkyl, cyanoalkyl, aryl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl, cyanocycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)R¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ (provided that R¹⁵ isnot H), —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and a heterocycloalkenylgroup (i.e., a heterocyclic group that has at least one, and preferablyone, double bond in a ring, e.g.,

and provided that the carbon atom to which the cyano (CN) group is boundto does not also have bound to said carbon atom a substituent selectedfrom the group consisting of: hydroxy, alkoxy, amino, halogen,—NHC(O)NR¹⁵R¹⁶ and —NHC(O)OR¹⁵;

(or in another embodiment, (1) each R¹³ and R¹⁴ is independentlyselected from the group consisting of: H, unsubstituted or substitutedalkyl, unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, unsubstituted orsubstituted heterocyclic, unsubstituted or substituted fluoroalkyl, andunsubstituted or substituted heterocycloalkylalkyl (wherein“heterocyloalkyl” means heterocyclic); wherein there are 1 to 6substituents on said substituted R¹³ and R¹⁴ groups and each substituentis independently selected from the group consisting of: alkyl, —CF₃,—OH, alkoxy, aryl, arylalkyl, fluroalkyl, cycloalkyl, cycloalkylalkyl,heteroaryl, heteroarylalkyl, —N(R⁴⁰)₂, —C(O)R¹⁵, —C(O)NR¹⁵R¹⁶,—S(O)_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is not H, halogen,and —NHC(O)NR¹⁵R¹⁶; or (2) R¹³ and R¹⁴ taken together with the nitrogenthey are attached to in the groups —C(O)NR¹³R¹⁴ and —SO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered heterocyclic ring), said ring optionally containing oneadditional heteroatom selected from the group consisting of: O, S andNR¹⁸; wherein there are 1 to 3 substituents on the substituted cyclizedR¹³ and R¹⁴ groups (i.e., there is 1 to 3 substituents on the ringformed when the R¹³ and R¹⁴ groups are taken together with the nitrogento which they are bound) and each substituent is independently selectedfrom the group consisting of: alkyl, aryl, hydroxy, hydroxyalkyl,alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ (provided that R¹⁵ is notH), —NHC(O)NR¹⁵R¹⁶, —NHC(O)OR¹⁵, halogen, and a heterocycloalkenyl group(i.e., a heterocyclic group that has at least one, and preferably one,double bond in a ring, e.g.,

each R¹⁵ and R¹⁶ is independently selected from the group consisting of:H, alkyl, aryl, arylalkyl, cycloalkyl and heteroaryl;

R¹⁷ is selected from the group consisting of: —SO₂alkyl, —SO₂aryl,—SO₂cycloalkyl, and —SO₂heteroaryl;

R¹⁸ is selected from the group consisting of: H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰;

each R¹⁹ and R²⁰ is independently selected from the group consisting of:alkyl, aryl and heteroaryl;

R³⁰ is selected from the group consisting of: alkyl, cycloalkyl, —CN,—NO₂, or —SO₂R¹⁵ provided that R¹⁵ is not H;

each R³¹ is independently selected from the group consisting of:unsubstituted alkyl, unsubstituted or substituted aryl, unsubstituted orsubstituted heteroaryl and unsubstituted or substituted cycloalkyl;wherein there are 1 to 6 substituents on said substituted R³¹ groups andeach substituent is independently selected from the group consisting of:alkyl, halogen and —CF₃;

each R⁴⁰ is independently selected from the group consisting of: H,alkyl and cycloalkyl; and

t is 0, 1 or 2.

Compounds of formula IA include compounds of formula IA.1:

wherein A, B, and R⁵⁰ are as described for compounds of formula IA.

Compounds of formula IA also include compounds of formula IA.2:

wherein A, B, and R⁵⁰ are as described for compounds of formula IA.

The descriptions of the compounds of formula IA below apply equally aswell to the compounds of formula IA.1 unless otherwise indicated.

The descriptions of the compounds of formula IA below also apply equallyas well to the compounds of formula IA.2 unless otherwise indicated.

For compounds of formula IA, when R³ is —SO_((t))NR¹³R¹⁴ (e.g.,—SO₂NR¹³R¹⁴), preferably R¹³ and R¹⁴ are independently selected from thegroup consisting of: H and alkyl (e.g., methyl, ethyl, isopropyl andt-butyl). Examples include, but are not limited to (1) —SO₂NH₂ and (2)—SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same or different alkyl group(e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkylgroup, such as, for example —SO₂N(CH₃)₂.

For compounds of formula IA, when R³ is —C(O)NR¹³R¹⁴, preferably R¹³ andR¹⁴ are independently selected from the group consisting of: H and alkyl(e.g., methyl, ethyl, isopropyl and t-butyl). Examples include, but arenot limited to —C(O)NR¹³R¹⁴ wherein each R¹³ and R¹⁴ are the same ordifferent alkyl group, e.g., the same alkyl group, such as, for example—C(O)N(CH₃)₂.

For the compounds of formula IA substituent A is preferably selectedfrom the group consisting of:

-   -   (1) unsubstituted or substituted:

wherein all substitutents are as defined for formula IA.

For the compounds of formula IA substituent A is most preferably:

wherein the furan ring is unsubstituted or substituted with 1 or 2 alkylgroups (e.g., C₁ to C₃ alkyl groups) wherein each alkyl group isindependently selected, R⁷ is selected from the group consisting of:—CF₃, alkyl (e.g., C₁ to C₄ alkyl) and cycloalkyl (e.g., cyclopropyl),and R⁸ is H. More preferably the furan ring is substituted.

For the compounds of formula IA substituent A is even more preferably:

wherein the furan ring is unsubstituted or substituted with 1 or 2 alkylgroups independently selected from the group consisting of methyl, ethyland isoprpyl, R⁷ is selected from the group consisting of: —CF₃, ethyl,isopropyl, t-butyl and cyclopropyl, and R⁸ is H. Still more preferablythe furan ring is substituted.

For the compounds of formula IA substituent A is even yet morepreferably:

wherein the furan ring is substituted with 1 or 2 alkyl groupsindependently selected from the group consisting of methyl, ethyl andisopropyl, R⁷ is selected from the group consisting of: ethyl, isopropyland t-butyl, and R⁸ is H.

Examples of substituent A in formula IA include, but are not limited to:

Substituent A in formula IA is most preferably selected from the groupconsisting of:

Substituent A in formula IA is more preferably selected from the groupconsisting of:

Substituent A in formula IA is even more preferably selected from thegroup consisting of:

Substituent B in formula IA is preferably selected from the groupconsisting of:

wherein all substituents are as defined for formula IA.

Substituent B in formula IA is most preferably selected from the groupconsisting of:

Substituent B in Formula IA is more preferably selected from the groupconsisting of:

Substituent B in Formula IA is even more preferably selected from thegroup consisting of:

Substituent B in Formula IA is still even more preferably selected fromthe group consisting of:

An embodiment of the present invention is directed to a method oftreating an chemokine mediated disease or condition in a patient in needof such treatment (e.g., a mammal, preferably a human being) comprisingadministering to said patient a therapeutically effective amount of atleast one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt thereof.

Examples of chemokine mediated (e.g., CXCR1 and/or CXCR2, or CCR7)diseases or conditions include but are not limited to: pain (e.g., acutepain, acute inflammatory pain, chronic inflammatory pain, andneuropathic pain), rheumatoid arthritis, acute inflammatory pain,chronic inflammatory pain, psoriasis, atopic dermatitis, asthma, COPD,adult respiratory disease, arthritis, inflammatory bowel disease,Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gramnegative sepsis, toxic shock syndrome, stroke, ischemia reperfusioninjury, renal reperfusion injury, glomerulonephritis, thrombosis,Alzheimer's disease, graft vs. host reaction (i.e., graft vs. hostdisease), allograft rejections (e.g., acute allograft rejection, andchronic allograft rejection), malaria, acute respiratory distresssyndrome, delayed type hypersensitivity reaction, atherosclerosis,cerebral ischemia, cardiac ischemia, osteoarthritis, multiple sclerosis,restinosis, angiogenesis, osteoporosis, gingivitis, respiratory viruses,herpes viruses, hepatitis viruses, HIV, Kaposi's sarcoma associatedvirus (i.e., Kaposi's sarcoma), meningitis, cystic fibrosis, pre-termlabor, cough, pruritis, multi-organ dysfunction, trauma, strains,sprains, contusions, psoriatic arthritis, herpes, encephalitis, CNSvasculitis, traumatic brain injury, CNS tumors, subarachnoid hemorrhage,post surgical trauma, interstitial pneumonitis, hypersensitivity,crystal induced arthritis, acute pancreatitis, chronic pancreatitis,acute alcoholic hepatitis, necrotizing enterocolitis, chronic sinusitis,angiogenic ocular disease, ocular inflammation, retinopathy ofprematurity, diabetic retinopathy, macular degeneration with the wettype preferred, corneal neovascularization, polymyositis, vasculitis,acne, gastric ulcers, duodenal ulcers, celiac disease, esophagitis,glossitis, airflow obstruction, airway hyperresponsiveness (i.e., airwayhyperreactivity), bronchiectasis, bronchiolitis, bronchiolitisobliterans, chronic bronchitis, cor pulmonae, dyspnea, emphysema,hypercapnea, hyperinflation, hypoxemia, hyperoxia-induced inflammations,hypoxia, surgical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertrophy, peritonitis associated withcontinuous ambulatory peritoneal dialysis (CAPD), granulocyticehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusionmismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burntherapy (i.e., the treatment of burns), periodontitis, cancer,transplant reperfusion injury, early transplantation rejection (e.g.,acute allograft rejection), airway hyperreactivity, allergic contactdermatitis, allergic rhinitis, alopecia areata, antiphospholipidsyndromes, aplastic anemia, autoimmune deafness (including, for example,Meniere's disease), autoimmune hemolytic syndromes, autoimmunehepatitis, autoimmune neuropathy, autoimmune ovarian failure, autoimmuneorchitis, autoimmune thrombocytopenia, bullous pemphigoid, chronicallograft vasculopathy, chronic inflammatory demyelinatingpolyneuropathy, cirrhosis, cor pneumoniae, cryoglobulinemia,dermatomyositis, diabetes, drug-induced autoimmunity, epidermolysisbullosa acquisita, endometriosis, fibrotic diseases, gastritis,Goodpasture's syndrome, Graves' disease, Gullain-Barre disease,Hashimoto's thyroiditis, hepatitis-associated autoimmunity, HIV-relatedautoimmune syndromes and hematologic disorders, hypophytis, idiopathicthrombocytic pupura, interstitial cystitis, juvenile arthritis,Langerhans' cell histiocytitis, lichen planus, metal-inducedautoimmunity, myasthenia gravis, myelodysplastic syndromes, myocarditis(including viral myocarditis), myositis, Neuropathies (including, forexample, IgA neuropathy, membranous neuropathy and idiopathicneuropathy), nephritic syndrome, optic neuritis, pancreatitis,paroxysmal nocturnal hemoglobulinemia, pemphigus, polymyalgia,post-infectious autoimmunity, primary biliary cirrhosis, reactivearthritis, ankylosing spondylitis, Raynaud's phenomenon, Reiter'ssyndrome, reperfusion injury, scleritis, scleroderma, secondaryhematologic manifestation of autoimmune diseases (such as, for example,anemias), silicone implant associated autoimmune disease, Sjogren'ssyndrome, systemic lupus erythematosus, thrombocytopenia, transversemyelitis, tubulointerstitial nephritis, uveitis, vasculitis syndromes(such as, for example, giant cell arteritis, Behcet's disease andWegener's granulomatosis), and Vitiligo.

Examples of CXCR1 and/or CXCR2 mediated diseases or conditions includebut are not limited to: pain (e.g., acute pain, acute inflammatory pain,chronic inflammatory pain, and neuropathic pain), acute inflammation,chronic inflammation, rheumatoid arthritis, psoriasis, atopicdermatitis, asthma, COPD, adult respiratory disease, arthritis,inflammatory bowel disease, Crohn's disease, ulcerative colitis, septicshock, endotoxic shock, gram negative sepsis, toxic shock syndrome,stroke, ischemia reperfusion injury, renal reperfusion injury,glomerulonephritis, thrombosis, Alzheimer's disease, graft vs. hostreaction (i.e., graft vs. host disease), allograft rejections (e.g.,acute allograft rejection, and chronic allograft rejection), malaria,acute respiratory distress syndrome, delayed type hypersensitivityreaction, atherosclerosis, cerebral ischemia, cardiac ischemia,osteoarthritis, multiple sclerosis, restinosis, angiogenesis,osteoporosis, gingivitis, respiratory viruses, herpes viruses, hepatitisviruses, HIV, Kaposi's sarcoma associated virus (i.e., Kaposi'ssarcoma), meningitis, cystic fibrosis, pre-term labor, cough, pruritis,multi-organ dysfunction, trauma, strains, sprains, contusions, psoriaticarthritis, herpes, encephalitis, CNS vasculitis, traumatic brain injury,CNS tumors, subarachnoid hemorrhage, post surgical trauma, interstitialpneumonitis, hypersensitivity, crystal induced arthritis, acutepancreatitis, chronic pancreatitis, acute alcoholic hepatitis,necrotizing enterocolitis, chronic sinusitis, angiogenic ocular disease,ocular inflammation, retinopathy of prematurity, diabetic retinopathy,macular degeneration with the wet type preferred, cornealneovascularization, polymyositis, vasculitis, acne, gastric ulcers,duodenal ulcers, celiac disease, esophagitis, glossitis, airflowobstruction, airway hyperresponsiveness (i.e., airway hyperreactivity),bronchiectasis, bronchiolitis, bronchiolitis obliterans, chronicbronchitis, cor pulmonae, dyspnea, emphysema, hypercapnea,hyperinflation, hypoxemia, hyperoxia-induced inflammations, hypoxia,surgical lung volume reduction, pulmonary fibrosis, pulmonaryhypertension, right ventricular hypertrophy, peritonitis associated withcontinuous ambulatory peritoneal dialysis (CAPD), granulocyticehrlichiosis, sarcoidosis, small airway disease, ventilation-perfusionmismatching, wheeze, colds, gout, alcoholic liver disease, lupus, burntherapy (i.e., the treatment of burns), periodontitis, cancer,transplant reperfusion injury, early transplantation rejection (e.g.,acute allograft rejection).

Examples of CCR7 mediated diseases or conditions include, but are notlimited to: pain (e.g., acute pain, acute inflammatory pain, chronicinflammatory pain, and neuropathic pain), acute inflammation, chronicinflammation, acute allograft rejection, acute respiratory distresssyndrome, adult respiratory disease, airway hyperreactivity, allergiccontact dermatitis, allergic rhinitis, alopecia areata, alzheimer'sdisease, angiogenic ocular disease, antiphospholipid syndromes, aplasticanemia, asthma, atherosclerosis, atopic dermatitis, autoimmune deafness(including, for example, Meniere's disease), autoimmune hemolyticsyndromes, autoimmune hepatitis, autoimmune neuropathy, autoimmuneovarian failure, autoimmune orchitis, autoimmune thrombocytopenia,bronchiolitis, bronchiolitis obliterans syndrome, bullous pemphigoid,burn therapy (i.e., the treatment of burns), cancer, cerebral ischemia,cardiac ischemia, chronic allograft rejection, chronic allograftvasculopathy, chronic bronchitis, chronic inflammatory demyelinatingpolyneuropathy, chronic sinusitis, cirrhosis, CNS vasculitis, COPD, Corpneumoniae, Crohn's disease, cryoglobulinemia, crystal-inducedarthritis, delayed-type hypersensitivity reactions, dermatomyositis,diabetes, diabetic retinopathy, drug-induced autoimmunity, dyspnea,emphysema, epidermolysis bullosa acquisita, endometriosis, fibroticdiseases, gastritis, glomerulonephritis, Goodpasture's syndrome, graftvs host disease, Graves' disease, Gullain-Barre disease, Hashimoto'sthyroiditis, hepatitis-associated autoimmunity, HIV-related autoimmunesyndromes and hematologic disorders, hyperoxia-induced inflammation,hypercapnea, hyperinflation, hypophytis, hypoxia, idiopathicthrombocytic pupura, inflammatory bowel diseases, interstitial cystitis,interstitial pneumonitis, juvenile arthritis, Langerhans' cellhistiocytitis, lichen planus, metal-induced autoimmunity, multiplesclerosis, myasthenia gravis, myelodysplastic syndromes, myocarditisincluding viral myocarditis, myositis, neuropathies (including, forexample, IgA neuropathy, membranous neuropathy and idiopathicneuropathy), nephritic syndrome, ocular inflammation, optic neuritis,osteoarthritis, pancreatitis, paroxysmal nocturnal hemoglobulinemia,pemphigus, polymyalgia, polymyositis, post-infectious autoimmunity,pulmonary fibrosis, primary biliary cirrhosis, psoriasis, pruritis,rheumatoid arthritis, reactive arthritis, ankylosing spondylitis,psoriatic arthritis, Raynaud's phenomenon, Reiter's syndrome,reperfusion injury, restenosis, sarcoidosis, scleritis, scleroderma,secondary hematologic manifestation of autoimmune diseases (such as, forexample, anemias), silicone implant associated autoimmune disease,Sjogren's syndrome, systemic lupus erythematosus, thrombocytopenia,thrombosis, transverse myelitis, tubulointerstitial nephritis,ulcerative colitis, uveitis, vasculitis and vasculitis syndromes (suchas, for example, giant cell arteritis, Behcet's disease and Wegener'sgranulomatosis), and vitiligo.

Another embodiment of this invention is directed to a method of treatinga CXCR1 and/or CXCR2 mediated disease, as described above, in a patientin need of such treatment comprising administering to said patient aneffective amount of a compound selected from the group consisting of thefinal compounds of Examples 2 and 6, and the pharmaceutically acceptablesalts thereof.

In another embodiment this invention is directed to a method of treatingpain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of this invention, or a pharmaceutically acceptable saltthereof. Examples of pain include, but are not limited to, the painassociated with: allodynia, ankylosing spondylitis, appendicitis,autoimmune disorders, bacterial infections, Behcet's syndrome, brokenbones, bronchitis, burns, bursitis, cancer including metastatic cancer,candidiasis, cardiovascular conditions, casualgia, chemical injury,childbirth (e.g., labor), chronic regional neuropathies, Crohn'sdisease, colorectal cancer, connective tissue injuries, conjunctivitis,COPD, decreased intracranial pressure, dental procedures, dermatitis,diabetes, diabetic neuropathy, dysesthesia, dysmenorrhea, eczema,emphysema, fever, fibromyalgia, gastric ulcer, gastritis, giant cellarteritis, gingivitis, gout, gouty arthritis, headache, headache painresulting from lumbar puncture, headaches including migraine headache,herpes simplex virus infections, HIV, Hodgkin's disease, hyperalgesia,hypersensitivity, inflammatory bowel disease, increased intracranialpressure, irritable bowel syndrome, ischemia, juvenile arthritis, kidneystones, lumbar spondylanhrosis, lower back, upper back and lumbrosacralconditions, lumbar spondylarthrosis, menstrual cramps, migraines, minorinjuries, multiple sclerosis, myasthenia gravis, myocarditis, musclestrains, musculoskeletal conditions, myocardial ischemia, nephriticsyndrome, nerve root avulsion, neuritis, nutritional deficiency, ocularand corneal conditions, ocular photophobia, ophthalmic diseases,osteoarthritis, otic surgery, otitis externa, otitis media,periarteritis nodosa, peripheral neuropathies, phantom limb pain,polymyositis, post-herpetic neuralgia, post-operative/surgical recovery,post-thoracotomy, psoriatic arthritis, pulmonary fibrosis, pulmonaryedema, radiculopathy, reactive arthritis, reflex sympathetic dystrophy,retinitis, retinopathies, rheumatic fever, rheumatoid arthritis,sarcoidosis, sciatica, scleroderma, sickle cell anemia, sinus headaches,sinusitis, spinal cord injury, spondyloarthropathies, sprains, stroke,swimmer's ear, tendonitis, tension headaches, thalamic syndrome,thrombosis, thyroiditis, toxins, traumatic injury, trigeminal neuralgia,ulcerative colitis, urogenital conditions, uveitis, vaginitis, vasculardiseases, vasculitis, viral infections and/or wound healing.

In another embodiment this invention is directed to a method of treatingpain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of this invention, or the pharmaceutically acceptablesalts thereof, and administering to said patient a therapeuticallyeffective amount of at least one medicament selected from the groupconsisting of: NSAIDs, COXIB inhibitors, anti-depressants andanti-convulsants. Examples of the pain treatable are described above.

In another embodiment this invention is directed to a method of treatingpain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of this invention, or the pharmaceutically acceptablesalts thereof, and administering to said patient a therapeuticallyeffective amount of at least one NSAIDs. Examples of the pain treatableare described above.

In another embodiment this invention is directed to a method of treatingpain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of this invention, or the pharmaceutically acceptablesalts thereof, and administering to said patient a therapeuticallyeffective amount of at least one COXIB inhibitor. Examples of the paintreatable are described above.

In another embodiment this invention is directed to a method of treatingpain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of this invention, or the pharmaceutically acceptablesalts thereof, and administering to said patient a therapeuticallyeffective amount of at least one anti-depressant. Examples of the paintreatable are described above.

In another embodiment this invention is directed to a method of treatingpain in a patient in need of such treatment comprising administering tosaid patient a therapeutically effective amount of at least one (usuallyone) compound of this invention, or the pharmaceutically acceptablesalts thereof, and administering to said patient a therapeuticallyeffective amount of at least one anti-convulsant. Examples of the paintreatable are described above.

In general the compounds of this invention used to treat pain will haveCXCR2 antagonistic activity.

NSAIDs are well known to those skilled in the art and can be used intheir known dosages and dosage regimens. Examples of NSAIDs include butare not limited to: piroxicam, ketoprofen, naproxen, indomethacin, andibuprofen

COXIB inhibitors are well known to those skilled in the art and can beused in their known dosages and dosage regimens. Examples of COXIBinhibitors include but are not limited to: rofecoxib and celecoxib.

Anti-depressants are well known to those skilled in the art and can beused in their known dosages and dosage regimens. Examples ofanti-depressants include but are not limited to: amitriptyline andnortriptyline.

Anti-convulsants are well known to those skilled in the art and can beused in their known dosages and dosage regimens. Examples ofAnti-convulsants include but are not limited to: gabapentin,carbamazepine, pregabalin, and lamotragine.

Another embodiment of this invention is directed to a method of treatingKaposi's sarcoma, melanoma, gastric carcinoma, and non-small cellcarcinoma in a patient in need of such treatment comprisingadministering to said patient an effective amount of at least one (e.g.,1-3, usually 1) compound of formula IA, or a pharmaceutically acceptablesalt thereof.

Another embodiment of this invention is directed to a method of treatingmelanoma, gastric carcinoma, and non-small cell carcinoma in a patientin need of such treatment comprising administering to said patient aneffective amount of at least one (e.g., 1-3, usually 1) compound offormula IA, or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is directed to a method oftreating cancer in a patient (e.g., a mammal, such as a human being) inneed of such treatment, comprising administering to said patient,concurrently or sequentially, a therapeutically effective amount of (a)at least one (e.g., 1-3, and usually one) compound of formula IA, or apharmaceutically acceptable salt thereof, and (b) at least one (e.g., 1,2 or 3) anticancer agent selected from the group consisting of: (1)microtubule affecting agents, (2) antineoplastic agents, (3)anti-angiogenesis agents, (4) VEGF receptor kinase inhibitors, (5)antibodies against the VEGF receptor, (6) interferon, and (7) radiation.

In further embodiments of this invention that are directed to thetreatment of cancer, at least one (e.g., 1-3, and usually one) compoundof formula IA, or a pharmaceutically acceptable salt thereof, isadministered in combination with at least one (e.g., 1 or 2, or 1)antineoplastic agent selected from the group consisting of: gemcitabine,paclitaxel (Taxol®), 5-Fluorouracil (5-FU), cyclophosphamide (Cytoxan®),temozolomide, taxotere and Vincristine.

In another embodiment the present invention provides a method oftreating cancer in a patient (e.g., a mammal, such as a human being) inneed of such treatment, comprising administering, concurrently orsequentially, an effective amount of (a) at least one (e.g., 1-3,usually 1) compound of formula IA, or a pharmaceutically acceptable saltthereof, and (b) at least one (e.g., 1-3, usually 1) microtubuleaffecting agent (e.g., paclitaxel).

In the method of treating a pulmonary disease (e.g., COPD, asthma, orcystic fibrosis), at least one (usually 1) compound of formula IA, or apharmaceutically acceptable salt thereof, is administered in combinationwith at least one compound selected from the group consisting of:glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists,muscarinic M1 antagonists, muscarinic M3 antagonists, muscarinic M2agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotrieneantagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastaseinhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase Dinhibitors, histamine H1 antagonists, histamine H3 antagonists, dopamineagonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-bagonists, nociceptin agonists, expectorants, mucolytic agents,decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesionmolecule inhibitors, and growth hormones. Agents that belong to theseclasses include, but are not limited to, beclomethasone, mometasone,ciclesonide, budesonide, fluticasone, albuterol, salmeterol, formoterol,loratadine, desloratadine, tiotropium bromide, MSI-ipratropium bromide,montelukast, theophilline, cilomilast, roflumilast, cromolyn, ZD-4407,talnetant, LTB-019, revatropate, pumafentrine, CP-955, AR-C-89855,BAY-19-8004, GW-328267, QAB-149, DNK-333, YM-40461 and TH-9506 orpharmaceutically acceptable formulations thereof.

Representative embodiments of the novel compounds of this invention aredescribed below. The embodiments have been numbered for purposes ofreference thereto.

Embodiment No. 1 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 2 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 3 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 4 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 5 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 6 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 7 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 8 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 9 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 10 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 11 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 12 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 13 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 14 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 15 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 16 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 17 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 18 is directed to the novel compounds of formula IAwherein B is:

and all other substitutents are as defined for of formula IA.

Embodiment No. 19 is directed to compounds of formula IA wherein B isselected from the group consisting of:

and R³ for this B group is selected from the group consisting of:—C(O)NR¹³R¹⁴,

and all other substituents are as defined for formula IA.

Embodiment No. 20 is directed to compounds of formula IA wherein B is:

and all other substituents are as defined in formula IA.

Embodiment No. 21 is directed to compounds of formula IA wherein B is

R¹³ and R¹⁴ are independently selected from the group consisting of Hand alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), and all othersubstituents are as defined in formula IA.

Embodiment No. 22 is directed to compounds of formula IA wherein B is

wherein:

-   -   (1) R² is —OH and all other substituents are as defined in        formula IA, or    -   (2) R² is —OH, and R¹³ and R¹⁴ are independently selected from        the group, consisting of: H and alkyl (e.g., methyl, ethyl,        isopropyl and t-butyl), or    -   (3) R² is —OH, and R¹³ and R¹⁴ are the same or different and        alkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), for        example the same alkyl group, for example methyl, and    -   (4) and all other substituents are as defined in formula IA.

Embodiment No. 23 is directed to compounds of formula IA wherein B is

R³ is selected from the group consisting of:

and all other substituents are as defined in formula IA.

Embodiment No. 24 is directed to compounds of formula IA wherein B is

R³ is selected from the group consisting of:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 25 is directed to compounds of formula IA wherein B is:

and all other substituents are as defined in formula IA.

Embodiment No. 26 is directed to compounds of formula IA wherein B is:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 27 is directed to compounds of formula IA wherein B is:

R² is as defined for compounds of formula IA, R¹³ and R¹⁴ areindependently selected from the group consisting of H and alkyl (e.g.,methyl, ethyl, isopropyl and t-butyl), and all other substituents areasdefined for compounds of formula IA. For example, R¹³ and R¹⁴ are thesame or different alkyl group. Also, for example, R¹³ and R¹⁴ are thesame alkyl group. Also, for example, R¹³ and R¹⁴ are methyl.

Embodiment No. 28 is directed to the novel compounds of formula IAwherein B is:

R² is —OH, R¹³ and R¹⁴ are independently selected from the groupconsisting of H and alkyl (e.g., methyl, ethyl, isopropyl and t-butyl),and all other substituents areas defined for compounds of formula IA.For example, R¹³ and R¹⁴ are the same or different alkyl group. Also,for example, R¹³ and R¹⁴ are the same alkyl group. Also, for example,R¹³ and R¹⁴ are methyl.

Embodiment No. 29 is directed to novel compounds of formula IA wherein Bis as described in Embodiment No. 23, R⁴ is H, R⁵ is H, R⁶ is H, and allother substituents are as defined for compounds of formula IA.

Embodiment No. 30 is directed to novel compounds of formula IA wherein Bis as described in Embodiment No. 24, R⁴ is H, R⁵ is H, R⁶ is H, and allother substituents areas defined for compounds of formula IA.

Embodiment No. 31 is directed to novel compounds of formula IA wherein Bis as described in Embodiments Nos. 21, 22, 25 and 26, except that R¹³and R¹⁴ are each methyl, and all other substituents are as defined informula IA.

Embodiment No. 32 is directed to compounds of formula IA wherein B is:

R¹¹ is H or methyl (preferably H), and all other substituents are asdefined in formula IA.

Embodiment No. 33 is directed to compounds of formula IA wherein B is:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 34 is directed to compounds of formula IA wherein B is:

R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined in formulaIA.

Embodiment No. 35 is directed to compounds of formula IA wherein B is:

R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituents are asdefined in formula IA.

Embodiment No. 36 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, and all other substituents are as definedin formula IA.

Embodiment No. 37 of this invention is directed to compounds of formulaIA wherein B is:

R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all othersubstituents are as defined in formula IA.

Embodiment No. 38 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H or methyl (preferably H), andall other substituents are as defined in formula IA.

Embodiment No. 39 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H or methyl(preferably H), and all other substituents are as defined in formula IA.

Embodiment No. 40 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H or methyl (preferably H), andR¹³ and R¹⁴ are independently selected from the group consisting of: H,alkyl (e.g., methyl, ethyl, isopropyl and t-butyl), unsubstitutedcycloalkyl, substituted cycloalkyl, unsubstituted heteroaryl andsubstituted heteroaryl, and all other substituents are as defined informula IA. For example, one of R¹³ or R¹⁴ is alkyl (e.g., methyl). Anexample of a substituted heteroaryl group is

Embodiment No. 41 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H or methyl(preferably H), and R¹³ and R¹⁴ are independently selected from thegroup consisting of:H, alkyl (e.g., methyl, ethyl, isopropyl, andt-butyl), unsubstituted cycloalkyl, and substituted cycloalkyl, and allother substituents are as defined in formula IA. For example R³ is (1)—SO₂NH₂ or (2) —SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same or differentalkyl group (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the samealkyl group, such as, for example —SO₂N(CH₃)₂.

Embodiment No. 42 is directed to compounds of formula IA wherein B is:

R¹¹ is H, and all other substituents are as defined in formula IA.

Embodiment No. 43 is directed to compounds of formula IA wherein B is:

R² is —OH, and all other substituents are as defined in formula IA.

Embodiment No. 44 is directed to compounds of formula IA wherein B is:

R³ is —C(O)NR¹³R¹⁴, and all other substituents are as defined in formulaIA.

Embodiment No. 45 is directed to compounds of formula IA wherein B is:

R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all other substituents are asdefined in formula IA.

Embodiment No. 46 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, and all other substituents are as definedin formula IA.

Embodiment No. 47 of this invention is directed to compounds of formulaIA wherein B is:

R² is —OH, and R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), and all othersubstituents are as defined in formula IA.

Embodiment No. 48 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and all other substituents areas defined in formula IA.

Embodiment No. 49 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, and allother substituents are as defined in formula IA.

Embodiment No. 50 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —C(O)NR¹³R¹⁴, R¹¹ is H, and R¹³ and R¹⁴ areindependently selected from the group consisting of: alkyl,unsubstituted heteroaryl and substituted heteroaryl, and all othersubstituents are as defined in formula IA. For example, one of R¹³ orR¹⁴ is alkyl (e.g., methyl). An example of a substituted heteroarylgroup is

Embodiment No. 51 is directed to compounds of formula IA wherein B is:

R² is —OH, R³ is —S(O)_(t)NR¹³R¹⁴ (e.g., t is 2), R¹¹ is H, R¹³ and R¹⁴are independently selected from the group consisting of:H and alkyl(e.g., methyl, ethyl, isopropyl, and t-butyl), and all othersubstituents are as defined in formula IA. For example R³ is (1) —SO₂NH₂and (2) —SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ are the same or different alkylgroup (e.g., methyl, ethyl, isopropyl and t-butyl), e.g., the same alkylgroup, such as, for example —SO₂N(CH₃)₂.

Embodiment No. 52 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for the compoundsof formula IA.

Embodiment No. 53 is directed to compounds of formula IA whereinsubstituent B in formula is selected from the group consisting of:

wherein

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ or and—NHSO₂R¹³;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂, cyano,—C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃,halogen, and —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano;

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

each R¹⁰ and R¹¹ is independently selected from the group consisting of:R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³,—SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR ¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴,—CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom the group consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected fromthe group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹and —C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selectedfrom the group consisting of: alkyl, aryl and heteroaryl; wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., the substituents on the ring formed when R¹³ and R¹⁴ are takentogether with the nitrogen to which they are bound) and each substituentis independently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 54 is directed to compounds of formula IA whereinsubstituent B in formula selected from the group consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or—CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴,—CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom O, S or NR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰is independently selected from alkyl, aryl and heteroaryl, wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., on the ring formed when R¹³ and R¹⁴ are taken together with thenitrogen to which they are bound) and each substituent is independentlyselected from the group consisting of: alkyl, aryl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting of: H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 55 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴ —SO₂NR¹³R¹⁴,—NO₂, cyano, and —SO₂R¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃ or—CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl and ethyl.

Embodiment No. 56 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

wherein:

R² is —OH;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and —CONR¹³R¹⁴;

R⁴ is selected form the group consisting of: H, —CH₃ and —CF₃;

R⁵ is selected from the group consisting of: H and cyano;

R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

R¹¹ is H; and

R¹³ and R¹⁴ are independently selected from the group consisting of Hand methyl (e.g., for —SO₂NR¹³R¹⁴ both R¹³ and R¹⁴ are H, or both R¹³and R¹⁴ are methyl, also, for example, for —CONR¹³R¹⁴ both R¹³ and R¹⁴are methyl).

Embodiment No. 57 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

wherein all substituents are as defined for formula IA.

Embodiment No. 58 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

Embodiment No. 59 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

Embodiment No. 60 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

Embodiment No. 61 is directed to compounds of formula IA whereinsubstituent B is selected from the group consisting of:

Embodiment No. 62 is directed to compounds of formula IA whereinsubstituent B is:

Embodiment No. 63 is directed to compounds of formula IA whereinsubstituent B is:

Embodiment No. 64 is directed to compounds of formula IA whereinsubstituent B is:

Embodiment No. 65 is directed to compounds of formula IA wherein:substituent A is selected from the group consisting of:

wherein the above rings are unsubstituted or substituted, as describedfor formula IA: and

wherein in (a) and (b): each R⁷ and R⁸ is independently selected fromthe group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA.

Embodiment No. 66 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g.,cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g.,cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g.,cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl).

Embodiment No. 67 is directed to the novel compounds of formula IAwherein substituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

wherein R⁷ is selected from the group consisting of: H, fluoroalkyl,alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H,alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined for formula IA.

Embodiment No. 68 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA.

Embodiment No. 69 is directed compounds of formula IA whereinsubstituent A is selected from the group consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA;

Embodiment No. 70 is directed compounds of formula IA whereinsubstituent A is selected from the group consisting of:

-   -   (1) unsubstituted or substituted:

wherein all substitutents are as defined for formula IA.

Embodiment No. 71 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

Embodiment No. 72 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

Embodiment No. 73 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

Embodiment No. 74 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

Embodiment No. 75 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

Embodiment No. 76 is directed to compounds of formula IA whereinsubstituent A is:

Embodiment No. 77 is directed to compounds of formula IA whereinsubstituent A is:

Embodiment No. 78 is directed to compounds of formula IA whereinsubstituent A is:

Embodiment No. 79 is directed to compounds of formula IA whereinsubstituent A is:

Embodiment No. 80 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

and substituent B is selected from the group consisting of:

Embodiment No. 81 is directed to compounds of formula IA whereinsubstituent A is selected from the group consisting of:

and substituent B is selected from the group consisting of:

Embodiment No. 82 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 64, and A is asdefined in any one of the Embodiment Nos. 65 to 79.

Embodiment No. 83 is directed to compounds of formula IA wherein B is asdescribed in any one of the Embodiment Nos. 1 to 64, and A is:

and all other substituents are as defined for formula IA.

Embodiment No. 84 is directed to compounds of formula IA wherein B is asdescribed in any one of the Embodiment Nos. 1 to 64, and A is:

wherein R⁷ is H, and R⁸ is alkyl (e.g., methyl, ethyl, isopropyl,cyclopropyl and t-butyl), and all other substituents are as defined forformula IA.

Embodiment No. 85 is directed to compounds of formula IA wherein B is asdescribed in any one of the Embodiment Nos. 1 to 64, and A is:

and all other substituents are as defined for formula IA.

Embodiment No. 86 is directed to compounds of formula IA wherein B is asdescribed in any one of the Embodiment Nos. 1 to 64, and A is:

wherein the furan ring is unsubstituted or substituted as described inthe definition of A for formula IA, and all other substituents are asdefined for formula IA.

Embodiment No. 87 is directed to compounds of formula IA wherein B isdescribed in any one of the Embodiment Nos. 1 to 64, and A is

wherein the furan ring is substituted and all other substituents are asdefined for formula IA.

Embodiment No. 88 is directed to compounds of formula IA wherein B is asdescribed in any one of the Embodiment Nos. 1 to 64,and A is

wherein the furan ring is substituted with at least one (e.g., 1 to 3,or 1 to 2) alkyl group and all other substituents are as defined forformula IA.

Embodiment No. 89 is directed to compounds of formula IA wherein B is asdescribed in any one of the Embodiment Nos. 1 to 64, A is

wherein the furan ring is substituted with one alkyl group and all othersubstituents are as defined for formula IA.

Embodiment No. 90 is directed to compounds of formula IA wherein B is asdescribed in any one of the Embodiment Nos. 1 to 64, and A is

wherein the furan ring is substituted with one C₁ to C₃ alkyl group(e.g., methyl or isopropyl), and all other substituents are as definedfor formula IA.

Embodiment No. 91 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 64, and A is asdefined in any one of the Embodiment Nos. 86 to 90, except that R⁷ andR⁸ are the same or different and each is selected from the groupconsisting of: H and alkyl.

Embodiment No. 92 is directed to novel compounds of formula IA wherein Bis as described in any one of the Embodiment Nos. 1 to 64, and A is asdefined in any one of the Embodiment Nos. 86 to 90, except that R⁷ is H,and R⁸ is alkyl (e.g., ethyl or t-butyl).

Embodiment No. 93 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group        consisting of:

wherein the above rings are unsubstituted or substituted, as describedfor formula IA: and

wherein in (a) and (b) above: each R⁷ and R⁸ is independently selectedfrom the group consisting of: H, unsubstituted or substituted alkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, unsubstituted or substituted arylalkyl, unsubstituted orsubstituted heteroarylalkyl, unsubstituted or substituted cycloalkyl,unsubstituted or substituted cycloalkylalkyl, —CO₂R¹³, —CONR¹³R¹⁴,fluoroalkyl, alkynyl, alkenyl, and cycloalkenyl, wherein saidsubstituents on said R⁷ and R⁸ substituted groups are selected from thegroup consisting of: a) cyano, b) —CO₂R¹³, c) —C(O)NR¹³R¹⁴, d)—SO₂NR¹³R¹⁴, e) —NO₂, f) —CF₃, g) —OR¹³, h) —NR¹³R¹⁴, i) —OC(O)R¹³, j)—OC(O)NR¹³R¹⁴, and k) halogen; and R^(8a) and R⁹ are as defined informula IA; and

-   -   (2) substituent B in formula IA is selected from the group        consisting of:

wherein R² to R⁶ and R¹⁰ to R¹⁴ are as defined above for the novelcompounds of formula IA.

Embodiment No. 94 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group        consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃, and—NO₂; each R⁷ and R⁸ is independently selected from the group consistingof: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl), fluoroalkyl(such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl, andcyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and R⁹ isselected from the group consisting of: H, halogen, alkyl, cycloalkyl,—CF₃, cyano, —OCH₃, and —NO₂; and

wherein each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); whereinR^(8a) is as defined in formula IA, and wherein R⁹ is selected from thegroup consisting of: H, halogen, alkyl, cycloalkyl, —CF₃, cyano, —OCH₃,and —NO₂; each R⁷ and R⁸ is independently selected from the groupconsisting of: H, alkyl (e.g., methyl, ethyl, t-butyl, and isopropyl),fluoroalkyl (such as, —CF₃ and —CF₂CH₃), cycloalkyl (e.g., cyclopropyl,and cyclohexyl), and cycloalkylalkyl (e.g., cyclopropylmethyl); and

-   -   (2) substituent B in formula IA is selected from the group        consisting of:

wherein

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ or and—NHSO₂R¹³;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴, —NO₂, cyano,—C(O)NR¹³R¹⁴, —SO₂R¹³; and —C(O)OR ¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, —CH₃,halogen, and —CF₃;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano;

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

each R¹⁰ and R¹¹ is independently selected from the group consisting of:R¹³, hydrogen, halogen, —CF₃, —NR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —C(O)OR¹³,—SH, —SO_((t))NR¹³R¹⁴, —SO₂R¹³, —NHC(O)R¹³, —NHSO₂NR¹³R¹⁴, —NHSO₂R¹³,—C(O)NR¹³R¹⁴, —C(O)NR¹³OR¹⁴, —OC(O)R¹³, —COR¹³, —OR¹³, and cyano;

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴,—CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom the group consisting of: O, S or NR¹⁸; wherein R¹⁸ is selected fromthe group consisting of: H, alkyl, aryl, heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹and —C(O)NR¹⁹R²⁰; wherein each R¹⁹ and R²⁰ is independently selectedfrom the group consisting of: alkyl, aryl and heteroaryl; wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., the substituents on the ring formed when R¹³ and R¹⁴ are takentogether with the nitrogen to which they are bound) and each substituentis independently selected from the group consisting of: alkyl, aryl,hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino,—C(O)OR¹⁵, —C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided thatR¹⁵ is not H, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶is independently selected from the group consisting: of H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 95 is directed to compounds of formula IA whereinsubstituent A in formula IA is even more preferably selected from thegroup consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, fluoroalkyl, alkyl andcycloalkyl; R⁸ is selected form the group consisting of: H, alkyl,—CF₂CH₃ and —CF₃; and R⁹ is selected from the group consisting of: H, F,Cl, Br, alkyl or —CF₃; and

wherein R⁷ is selected from the group consisting of: H, fluoroalkyl,alkyl and cycloalkyl; R⁸ is selected form the group consisting of: H,alkyl, —CF₂CH₃ and —CF₃; and R^(8a) is as defined for formula IA.

Embodiment No. 96 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group        consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: H, F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA.

-   -   (2) substituent B in formula IA is selected from the group        consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴,—NO₂, cyano, —SO₂R¹³; and —C(O)OR¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, alkyl(e.g., —CH₃ and ethyl), —CF₃, and halogen;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H, methyl, ethyl and isopropyl; or

R¹³ and R¹⁴ when taken together with the nitrogen they are attached toin the groups —NR¹³R¹⁴, —C(O)NR¹³R¹⁴, —SO₂NR¹³R¹⁴, —OC(O)NR¹³R¹⁴,—CONR¹³R¹⁴, —NR¹³C(O)NR¹³R¹⁴, —SO_(t)NR¹³R¹⁴, —NHSO₂NR¹³R¹⁴ form anunsubstituted or substituted saturated heterocyclic ring (preferably a 3to 7 membered ring) optionally having one additional heteroatom selectedfrom O, S or NR¹⁸ wherein R¹⁸ is selected from H, alkyl, aryl,heteroaryl, —C(O)R¹⁹, —SO₂R¹⁹ and —C(O)NR¹⁹R²⁰, wherein each R¹⁹ and R²⁰is independently selected from alkyl, aryl and heteroaryl, wherein thereare 1 to 3 substituents on the substituted cyclized R¹³ and R¹⁴ groups(i.e., on the ring formed when R¹³ and R¹⁴ are taken together with thenitrogen to which they are bound) and each substituent is independentlyselected from the group consisting of: alkyl, aryl, hydroxy,hydroxyalkyl, alkoxy, alkoxyalkyl, arylalkyl, fluoroalkyl, cycloalkyl,cycloalkylalkyl, heteroaryl, heteroarylalkyl, amino, —C(O)OR¹⁵,—C(O)NR¹⁵R¹⁶, —SO_(t)NR¹⁵R¹⁶, —C(O)R¹⁵, —SO₂R¹⁵ provided that R¹⁵ is notH, —NHC(O)NR¹⁵R¹⁶ and halogen; and wherein each R¹⁵ and R¹⁶ isindependently selected from the group consisting of: H, alkyl, aryl,arylalkyl, cycloalkyl and heteroaryl.

Embodiment No. 97 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group        consisting of:

wherein the above rings are unsubstituted, or the above rings aresubstituted with 1 to 3 substituents independently selected from thegroup consisting of: F, Cl, Br, alkyl, cycloalkyl, and —CF₃; R⁷ isselected from the group consisting of: H, —CF₃, —CF₂CH₃, methyl, ethyl,isopropyl, cyclopropyl and t-butyl; and R⁸ is H; and

wherein R⁷ is selected from the group consisting of: H, —CF₃, —CF₂CH₃,methyl, ethyl, isopropyl, cyclopropyl and t-butyl; and R⁸ is H; andR^(8a) is as defined for formula IA;

-   -   (2) substituent B in formula IA is selected from the group        consisting of:

wherein:

R² is selected from the group consisting of: H, OH, —NHC(O)R¹³ and—NHSO₂R¹³;

R³ is selected from the group consisting of: —C(O)NR¹³R¹⁴—SO₂NR¹³R¹⁴,—NO₂, cyano, and —SO₂R¹³;

R⁴ is selected from the group consisting of: H, —NO₂, cyano, alkyl(e.g., —CH₃ and ethyl), —CF₃ and halogen;

R⁵ is selected from the group consisting of: H, —CF₃, —NO₂, halogen andcyano; and

R⁶ is selected from the group consisting of: H, alkyl and —CF₃;

R¹¹ is selected from the group consisting of: H, halogen and alkyl; and

each R¹³ and R¹⁴ is independently selected from the group consisting of:H and unsubstituted alkyl (e.g., methyl and ethyl).

Embodiment No. 98 is directed to compounds of formula IA wherein:

-   -   (1) substituent A in formula IA is selected from the group        consisting of:

-   -   (2) substituent B in formula IA is selected from the group        consisting of:

wherein:

R² is —OH;

R³ is selected from the group consisting of: —SO₂NR¹³R¹⁴ and —CONR¹³R¹⁴;

R⁴ is selected form the group consisting of: H, Br, —CH₃, ethyl and—CF₃;

R⁵ is selected from the group consisting of: H and cyano;

R⁶ is selected from the group consisting of: H, —CH₃ and —CF₃;

R¹¹ is H; and

R¹³ and R¹⁴ are independently selected from the group consisting of Hand methyl (e.g., for —SO₂NR¹³R¹⁴ both R¹³ and R¹⁴ are H, or both R¹³and R¹⁴ are methyl, also, for example, for —CONR¹³R¹⁴ both R¹³ and R¹⁴are methyl).

Embodiment No. 99 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 70 and substituent B is asdefined in Embodiment No. 57.

Embodiment No. 100 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 70 and substituent B is asdefined in Embodiment No. 58.

Embodiment No. 101 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 70 and substituent B is asdefined in Embodiment No. 59.

Embodiment No. 102 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 71 and substituent B is asdefined in Embodiment No. 57.

Embodiment No. 103 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 71 and substituent B is asdefined in Embodiment No. 58.

Embodiment No. 104 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 71 and substituent B is asdefined in Embodiment No. 59.

Embodiment No. 105 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 72 and substituent B is asdefined in Embodiment No. 57.

Embodiment No. 106 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 72 and substituent B is asdefined in Embodiment No. 58.

Embodiment No. 107 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 72 and substituent B is asdefined in Embodiment No. 59.

Embodiment No. 108 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 73 and substituent B is asdefined in Embodiment No. 57.

Embodiment No. 109 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 73 and substituent B is asdefined in Embodiment No. 58.

Embodiment No. 110 is directed to compounds of formula IA whereinsubstituent A is as defined in Embodiment No. 73 and substituent B is asdefined in Embodiment No. 59.

Embodiment No. 111 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is H.

Embodiment No. 112 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)R¹³.

Embodiment No. 113 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)R¹³ and wherein R¹³ in said R⁵⁰ substituent isalkyl.

Embodiment No. 114 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)C₂H₅.

Embodiment No. 115 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)OR¹³.

Embodiment No. 116 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)OR¹³ and wherein R¹³ in said R⁵⁰ substituent isalkyl.

Embodiment No.117 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)OC₂H₅.

Embodiment No.117 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)NR¹³R¹⁴.

Embodiment No.118 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)NR¹³R⁴⁴ and wherein R¹³ and R¹⁴ in said R⁵⁰substituent are each independently selected from the group consistingof: H and alkyl.

Embodiment No.119 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)NH₂.

Embodiment No.120 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —C(O)N(CH₃)₂.

Embodiment No.121 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —S(O)₂NR ³R¹⁴.

Embodiment No.122 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —S(O)₂NR¹³R¹⁴ and wherein R¹³ and R¹⁴ in said R⁵⁰substituent are each independently selected from the group consistingof: H and alkyl.

Embodiment No.123 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —S(O)₂NH₂.

Embodiment No.124 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —CF₃.

Embodiment No. 125 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —CN.

Embodiment No.126 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —NO₂.

Embodiment No.127 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is —NR¹³R¹⁴.

Embodiment No. 128 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is R¹³.

Embodiment No. 129 is directed to any one of Embodiment Nos. 1 to 110wherein R⁵⁰ is halo (e.g., Cl or Br).

Embodiment No. 130 is directed to any one of Embodiment Nos. 1 to 129wherein the compound of formula IA is a compound of formula IA.1.

Embodiment No. 131 is directed to any one of Embodiment Nos. 1 to 129wherein the compound of formula IA is a compound of formula IA.2.

Embodiment No. 132 is directed to any one of the Embodiment Nos. 1 to131 wherein the compound of formula IA is a pharmaceutically acceptablesalt.

Embodiment No. 133 is directed to any one of the Embodiment Nos. 1 to131 wherein the compound of formula IA is a sodium salt.

Embodiment No. 134 is directed to any one of the Embodiment Nos. 1 to131 wherein the compound of formula IA is a calcium salt.

Embodiment No. 135 is directed to a pharmaceutically acceptable salt ofany one of the representative compounds of this invention that aredescribed below.

Embodiment No. 136 is directed to a sodium salt of any one of therepresentative compounds described below.

Embodiment No. 137 is directed to a calcium salt of any one of therepresentative compounds described below.

Embodiment No. 138 is directed to a pharmaceutical compositioncomprising at least one (e.g., 1 to 3, usually 1) compound of formula IAas described in any one of Embodiment Nos. 1 to 137 in combination witha pharmaceutically acceptable carrier (or diluent). When more than onecompound is used each compound is independently selected from the groupconsisting of Embodiment Nos. 1 to 137.

Embodiment No. 139 is directed to a method of treating any one of thediseases or conditions described herein (i.e., the chemokine mediateddiseases or conditions) comprising administering to a patient in need ofsuch treatment an effective amount (e.g., a therapeutically effectiveamount) of a compound of formula IA as described in any one of theEmbodiment Nos. 1 to 137.

Embodiment No. 140 is directed to a method of treating any one of thediseases described herein (i.e., the chemokine mediated diseases)comprising administering to a patient in need of such treatment aneffective amount (e.g., a therapeutically effective amount) of thepharmaceutical composition described in Embodiment No. 138.

Embodiment No. 141 is directed to a method of treating rheumatoidarthritis in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of atleast one (usually one) compound from any of Embodiment Nos. 1 to 137.When more than one compound is used each compound is independentlyselected from the group consisting of Embodiment Nos. 1 to 137.

Embodiment No. 142 is directed to a method of treating rheumatoidarthritis in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thepharmaceutical composition described in Embodiment No. 138.

Embodiment No. 143 is directed to a method of treating rheumatoidarthritis in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of atleast one (usually 1) compound from any of Embodiment Nos. 1 to 137 incombination with at least one compound selected from the groupconsisting of COX-2 inhibitors, COX inhibitors, immunosuppressives(e.g., methotrexate, cyclosporin, leflunimide and sulfasalazine),steroids (e.g., betamethasone, cortisone and dexamethasone), PDE IVinhibitors, anti-TNF-α compounds, MMP inhibitors, glucocorticoids,chemokine inhibitors, CB2-selective inhibitors, and other classes ofcompounds indicated for the treatment of rheumatoid arthritis. When morethan one compound of Embodiment Nos. 1 to 137 is used, each compound isindependently selected from said Embodiment Numbers.

Embodiment No. 144 is directed to a method of treating rheumatoidarthritis in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thepharmaceutical composition described in Embodiment 138 in combinationwith at least one compound selected from the group consisting of COX-2inhibitors, COX inhibitors, immunosuppressives (e.g., methotrexate,cyclosporin, leflunimide and sulfasalazine), steroids (e.g.,betamethasone, cortisone and dexamethasone), PDE IV inhibitors,anti-TNF-α compounds, MMP inhibitors, glucocorticoids, chemokineinhibitors, CB2-selective inhibitors, and other classes of compoundsindicated for the treatment of rheumatoid arthritis.

Embodiment No. 145 is directed to a method of treating COPD in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundfrom any of Embodiment Nos. 1 to 137. When more than one compound isused each compound is independently selected from. the group consistingof Embodiment Nos. 1 to 137.

Embodiment No. 146 is directed to a method of treating COPD in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of the pharmaceutical compositiondescribed in Embodiment 138.

Embodiment No. 147 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundfrom any of Embodiment Nos. 1 to 137. When more than one compound isused each compound is independently selected from the group consistingof Embodiment Nos. 1 to 137.

Embodiment No. 148 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of the pharmaceutical compositiondescribed in Embodiment 138.

Embodiment No. 149 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundfrom any of Embodiment Nos. 1 to 137, and administering atherapeutically effective amount of at least one medicament selectedfrom the group consisting of NSAIDs, COXIB inhibitors, anti-depressantsand anti-convulsants. When more than one compound is used each compoundis independently selected from the group consisting of Embodiment Nos. 1to 137.

Embodiment No. 150 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of the pharmaceutical compositiondescribed in Embodiment 138, and administering a therapeuticallyeffective amount of at least one medicament selected from the groupconsisting of NSAIDs, COXIB inhibitors, anti-depressants andanti-convulsants.

Embodiment No. 151 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundfrom any of Embodiment Nos. 1 to 137, and administering atherapeutically effective amount of at least one NSAID. When more thanone compound is used each compound is independently selected from thegroup consisting of Embodiment Nos. 1 to 137.

Embodiment No. 152 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of the pharmaceutical compositiondescribed in Embodiment 138, and administering a therapeuticallyeffective amount of at least one NSAID.

Embodiment No. 153 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundfrom any of Embodiment Nos. 1 to 137, and administering atherapeutically effective amount of at least one COXIB inhibitor. Whenmore than one compound is used each compound is independently selectedfrom the group consisting of Embodiment Nos. 1 to 137.

Embodiment No. 154 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of the pharmaceutical compositiondescribed in Embodiment 137, and administering a therapeuticallyeffective amount of at least one COXIB inhibitor.

Embodiment No. 155 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundfrom any of Embodiment Nos. 1 to 137, and administering atherapeutically effective amount of at least one anti-depressant. Whenmore than one compound is used each compound is independently selectedfrom the group consisting of Embodiment Nos. 1 to 137.

Embodiment No. 156 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of the pharmaceutical compositiondescribed in Embodiment 138, and administering a therapeuticallyeffective amount of at least one anti-depressant.

Embodiment No. 157 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of at least one (usually one) compoundfrom any of Embodiment Nos. 1 to 137, and administering atherapeutically effective amount of at least one anti-convulsant. Whenmore than one compound is used each compound is independently selectedfrom the group consisting of Embodiment Nos. 1 to 137.

Embodiment No. 158 is directed to a method of treating pain in a patientin need of such treatment comprising administering to said patient atherapeutically effective amount of the pharmaceutical compositiondescribed in Embodiment 138, and administering a therapeuticallyeffective amount of at least one anti-convusant.

Embodiment No. 159 is directed to a method of treating pain in any oneof Embodiment Nos. 149-152 wherein said NSAID is selected from the groupconsisting of: piroxicam, ketoprofen, naproxen, indomethacin, andibuprofen.

Embodiment No. 160 is directed to a method of treating pain in any oneof Embodiment Nos. 149, 150, 153 and 154 wherein said COXIB inhibitor isselected from the group consisting of: rofecoxib and celecoxib.

Embodiment No. 160 is directed to a method of treating pain in any oneof Embodiment Nos. 149, 150, 155 and 156 wherein said anti-depressant isselected from the group consisting of: amitriptyline and nortriptyline.

Embodiment No. 162 is directed to a method of treating pain in any oneof Embodiment Nos. 149, 150, 157 and 158 wherein said anti-convulsant isselected from the group consisting of: gabapentin, carbamazepine,pregabalin, and lamotragine.

Embodiment No. 163 is directed to a method of treating pain described byany one of Embodiment Nos. 147 to 162 wherein the pain treated is painassociated with: allodynia, ankylosing spondylitis, appendicitis,autoimmune disorders, bacterial infections, Behcet's syndrome, brokenbones, bronchitis, burns, bursitis, cancer including metastatic cancer,candidiasis, cardiovascular conditions, casualgia, chemical injury,childbirth (e.g., labor), chronic regional neuropathies, Crohn'sdisease, colorectal cancer, connective tissue injuries, conjunctivitis,COPD, decreased intracranial pressure, dental procedures, dermatitis,diabetes, diabetic neuropathy, dysesthesia, dysmenorrhea, eczema,emphysema, fever, fibromyalgia, gastric ulcer, gastritis, giant cellarteritis, gingivitis, gout, gouty arthritis, headache, headache painresulting from lumbar puncture, headaches including migraine headache,herpes simplex virus infections, HIV, Hodgkin's disease, hyperalgesia,hypersensitivity, inflammatory bowel disease, increased intracranialpressure, irritable bowel syndrome, ischemia, juvenile arthritis, kidneystones, lumbar spondylanhrosis, lower back, upper back and lumbrosacralconditions, lumbar spondylarthrosis, menstrual cramps, migraines, minorinjuries, multiple sclerosis, myasthenia gravis, myocarditis, musclestrains, musculoskeletal conditions, myocardial ischemia, nephriticsyndrome, nerve root avulsion, neuritis, nutritional deficiency, ocularand corneal conditions, ocular photophobia, ophthalmic diseases,osteoarthritis, otic surgery, otitis externa, otitis media,periarteritis nodosa, peripheral neuropathies, phantom limb pain,polymyositis, post-herpetic neuralgia, post-operative/surgical recovery,post-thoracotomy, psoriatic arthritis, pulmonary fibrosis, pulmonaryedema, radiculopathy, reactive arthritis, reflex sympathetic dystrophy,retinitis, retinopathies, rheumatic fever, rheumatoid arthritis,sarcoidosis, sciatica, scleroderma, sickle cell anemia, sinus headaches,sinusitis, spinal cord injury, spondyloarthropathies, sprains, stroke,swimmer's ear, tendonitis, tension headaches, thalamic syndrome,thrombosis, thyroiditis, toxins, traumatic injury, trigeminal neuralgia,ulcerative colitis, urogenital conditions, uveitis, vaginitis, vasculardiseases, vasculitis, viral infections and/or wound healing.

Embodiment No. 164 is directed to a method of treating acute pain in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound from any of Embodiment Nos. 1 to 137. When more than onecompound is used each compound is independently selected from the groupconsisting of Embodiment Nos. 1 to 137.

Embodiment No. 165 is directed to a method of treating acute pain in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the pharmaceuticalcomposition described in Embodiment No. 138.

Embodiment No. 166 is directed to a method of treating acuteinflammatory pain in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of atleast one (usually one) compound from any of Embodiment Nos. 1 to 137.When more than one compound is used each compound is independentlyselected from the group consisting of Embodiment Nos. 1 to 137.

Embodiment No. 167 is directed to a method of treating acuteinflammatory pain in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thepharmaceutical composition described in Embodiment No. 138.

Embodiment No. 168 is directed to a method of treating chronicinflammatory pain in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of atleast one (usually one) compound from any of Embodiment Nos. 1 to 137.When more than one compound is used each compound is independentlyselected from the group consisting of Embodiment Nos. 1 to 137.

Embodiment No. 169 is directed to a method of treating chronicinflammatory pain in a patient in need of such treatment comprisingadministering to said patient a therapeutically effective amount of thepharmaceutical composition described in Embodiment No. 138.

Embodiment No. 170 is directed to a method of treating neuropathic painin a patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound from any of Embodiment Nos. 1 to 137. When more than onecompound is used each compound is independently selected from the groupconsisting of Embodiment Nos. 1 to 137.

Embodiment No. 171 is directed to a method of treating neuropathic painin a patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the pharmaceuticalcomposition described in Embodiment No. 138.

Embodiment No. 172 is directed to a method of treating pain as describedin any of Embodiment Nos. 149 to 162 wherein said pain is acute pain.

Embodiment No. 173 is directed to a method of treating pain as describedin any of Embodiment Nos. 149 to 162 wherein said pain is acuteinflammatory pain.

Embodiment No. 174 is directed to a method of treating pain as describedin any of Embodiment Nos. 149 to 162 wherein said pain is chronicinflammatory pain.

Embodiment No. 175 is directed to a method of treating pain as describedin any of Embodiment Nos. 149 to 162 wherein said pain is neuropathicpain.

Embodiment No. 176 is directed to a method of treating arthritis in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound from any of Embodiment Nos. 1 to 137. When more than onecompound is used each compound is independently selected from the groupconsisting of Embodiment Nos. 1 to 137.

Embodiment No. 177 is directed to a method of treating arthritis in apatient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the pharmaceuticalcomposition described in Embodiment No. 138.

Embodiment No. 178 is directed to a method of treating osteoarthritis ina patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of at least one (usually one)compound from any of Embodiment Nos. 1 to 137. When more than onecompound is used each compound is independently selected from the groupconsisting of Embodiment Nos. 1 to 138.

Embodiment No. 179 is directed to a method of treating osteoarthritis ina patient in need of such treatment comprising administering to saidpatient a therapeutically effective amount of the pharmaceuticalcomposition described in Embodiment No. 138.

Representative compounds include the final compounds of Examples 1-6,100-119, 121-124, 129-150, 152-155, 160-181, 183-186, 191-213, 214-217,and 222-263, or the pharmaceutically acceptable salts thereof.

Preferred compounds of the invention are the final compounds of Examples1, 2, 6, 100, 101, 103, 104, 105, 107, 109, 110, 111, 113, 114, 115,117, 118, 119, 123, 129, 131, 132, 134, 136, 138, 140, 141, 144, 145,146, 148, 149, 162, 163, 165, 167, 173, 177, 194, 197, 198, 204, 208,225, 229, 235, 255, 256 or the pharmaceutically acceptable saltsthereof.

More preferred compounds of the invention are the final compounds ofExamples 1, 2, 6, 100, 101, 103, 104, 105, 109, 110, 111, 113, 114, 115,117, 118, 119, 129, 131, 132, 134, 136, 141, 146, 162, 163, 165, 167,173, 177, 194, 197, 198, 204, 208, 225, 229, 235, 255, 256, or thepharmaceutically acceptable salts thereof.

Most preferred compounds of the invention are the final compounds ofExamples 1, 2, 6, 100, 101, 104, 105, 111, 115, 119, 129, 132, 136, 229,235, 256, or the pharmaceutically acceptable salts thereof.

Certain compounds of the invention may exist in different stereoisomericforms (e.g., enantiomers, diastereoisomers and atropisomers). Theinvention contemplates all such stereoisomers both in pure form and inadmixture, including racemic mixtures. Isomers can be prepared usingconventional methods.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate” “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

Certain compounds will be acidic in nature, e.g. those compounds whichpossess a carboxyl or phenolic hydroxyl group. These compounds may formpharmaceutically acceptable salts. Examples of such salts may includesodium, potassium, calcium, aluminum, gold and silver salts. Alsocontemplated are salts formed with pharmaceutically acceptable aminessuch as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine andthe like.

Certain basic compounds also form pharmaceutically acceptable salts,e.g., acid addition salts. For example, the pyrido-nitrogen atoms mayform salts with strong acid, while compounds having basic substituentssuch as amino groups also form salts with weaker acids. Examples ofsuitable acids for salt formation are hydrochloric, sulfuric,phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric,succinic, ascorbic, maleic, methanesulfonic and other mineral andcarboxylic acids well known to those skilled in the art. The salts areprepared by contacting the free base form with a sufficient amount ofthe desired acid to produce a salt in the conventional manner. The freebase forms may be regenerated by treating the salt with a suitabledilute aqueous base solution such as dilute aqueous NaOH, potassiumcarbonate, ammonia and sodium bicarbonate. The free base forms differfrom their respective salt forms somewhat in certain physicalproperties, such as solubility in polar solvents, but the acid and basesalts are otherwise equivalent to their respective free base forms forpurposes of the invention.

All such acid and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Compounds of formula IA can exist in unsolvated and solvated forms(orcompounds of formula IA can optionally be converted to a solvate),including hydrated forms. In general, the solvated forms, withpharmaceutically acceptable solvents such as water, ethanol and thelike, are equivalent to the unsolvated forms for the purposes of thisinvention.

Preparation of solvates is generally known. Thus, for example, M. Cairaet al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describe thepreparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

This invention also includes Prodrugs of the novel compounds of thisinvention. The term “prodrug,” as used herein, represents compounds thatare rapidly transformed in vivo to the parent compound (i.e., a compoundof formula IA), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in EdwardB. Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, both of which areincorporated herein by reference.

This invention also includes the compounds of this invention in isolatedand pure form.

This invention also includes polymorphic forms of the compounds of thisinvention. The polymorphic forms of the compounds of formula IA, and ofthe salts, solvates and prodrugs of the compounds of formula IA, areintended to be included in the present invention.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington: The Science and Practice ofPharmacy, 20^(th) Edition, (2000), Lippincott Williams & Wilkins,Baltimore, Md.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal composition can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 0.01 mg to about 1000 mg, preferably fromabout 0.01 mg to about 750 mg, more preferably from about 0.01 mg toabout 500 mg, and most preferably from about 0.01 mg to about 250 mg,according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total dosage may bedivided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 0.04mg/day to about 4000 mg/day, in two to four divided doses.

Classes of compounds that can be used as the chemotherapeutic agent(antineoplastic agent) include: alkylating agents, antimetabolites,natural products and their derivatives, hormones and steroids (includingsynthetic analogs), and synthetics. Examples of compounds within theseclasses are given below.

Alkylating agents (including nitrogen mustards, ethyleniminederivatives, alkyl sulfonates, nitrosoureas and triazenes): Uracilmustard, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide,Melphalan, Chlorambucil, Pipobroman, Triethylene-melamine,Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine,Streptozocin, Dacarbazine, and Temozolomide.

Antimetabolites (including folic acid antagonists, pyrimidine analogs,purine analogs and adenosine deaminase inhibitors): Methotrexate,5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine,6-Thioguanine, Fludarabine phosphate, Pentostatine, and Gemcitabine.

Natural products and their derivatives (including vinca alkaloids,antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins):Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, paclitaxel(paclitaxel is commercially available as Taxol® and is described in moredetail below in the subsection entitled “Microtubule Affecting Agents”),Mithramycin, Deoxyco-formycin, Mitomycin-C, L-Asparaginase, Interferons(especially IFN-a), Etoposide, and Teniposide.

Hormones and steroids (including synthetic analogs):17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone,Fluoxymesterone, Dromostanolone propionate, Testolactone,Megestrolacetate, Tamoxifen, Methylprednisolone, Methyltestosterone,Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,Flutamide, Toremifene, Zoladex.

Synthetics (including inorganic complexes such as platinum coordinationcomplexes): Cisplatin, Carboplatin, Hydroxyurea, Amsacrine,Procarbazine, Mitotane, Mitoxantrone, Levamisole, andHexamethylmelamine.

Methods for the safe and effective administration of most of thesechemotherapeutic agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g.,Physician's Desk Reference, 57^(th) edition, 2003, Thompson PDR atMontvale, N.J. 07645-1742, USA; the disclosure of which is incorporatedherein by reference thereto.

As used herein, a microtubule affecting agent is a compound thatinterferes with cellular mitosis, i.e., having an anti-mitotic effect,by affecting microtubule formation and/or action. Such agents can be,for instance, microtubule stabilizing agents or agents that disruptmicrotubule formation.

Microtubule affecting agents useful in the invention are well known tothose of skill in the art and include, but are not limited toallocolchicine (NSC 406042), Halichondrin B (NSC 609395), colchicine(NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel(Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives (e.g., NSC608832), thiocolchicine (NSC 361792), trityl cysteine (NSC 83265),vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574),epothilone A, epothilone, and discodermolide (see Service, (1996)Science, 274:2009) estramustine, nocodazole, MAP4, and the like.Examples of such agents are also described in the scientific and patentliterature, see, e.g., Bulinski (1 997) J. Cell Sci. 110:3055-3064;Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564; Muhlradt (1997)Cancer Res. 57:3344-3346; Nicolaou (1997) Nature 387:268-272; Vasquez(1997) Mol. Biol. Cell. 8:973-985; Panda (1996) J. Biol. Chem.271:29807-29812.

Particularly preferred agents are compounds with paclitaxel-likeactivity. These include, but are not limited to paclitaxel andpaclitaxel derivatives (paclitaxel-like compounds) and analogues.Paclitaxel and its derivatives are available commercially. In addition,methods of making paclitaxel and paclitaxel derivatives and analoguesare well known to those of skill in the art (see, e.g., U.S. Pat. Nos.5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589;5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769;5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506).

More specifically, the term “paclitaxel” as used herein refers to thedrug commercially available as Taxol® (NSC number: 125973). Taxol®inhibits eukaryotic cell replication by enhancing polymerization oftubulin moieties into stabilized microtubule bundles that are unable toreorganize into the proper structures for mitosis. Of the many availablechemotherapeutic drugs, paclitaxel has generated interest because of itsefficacy in clinical trials against drug-refractory tumors, includingovarian and mammary gland tumors (Hawkins (1992) Oncology, 6: 17-23,Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J.Natl. Canc. Inst. 82: 1247-1259).

Additional microtubule affecting agents can be assessed using one ofmany such assays known in the art, e.g., a semiautomated assay whichmeasures the tubulin-polymerizing activity of paclitaxel analogs incombination with a cellular assay to measure the potential of thesecompounds to block cells in mitosis (see Lopes (1997) Cancer Chemother.Pharmacol. 41:37-47).

Generally, activity of a test compound is determined by contacting acell with that compound and determining whether or not the cell cycle isdisrupted, in particular, through the inhibition of a mitotic event.Such inhibition may be mediated by disruption of the mitotic apparatus,e.g., disruption of normal spindle formation. Cells in which mitosis isinterrupted may be characterized by altered morphology (e.g.,microtubule compaction, increased chromosome number, etc.).

Compounds with possible tubulin polymerization activity can be screenedin vitro. In a preferred embodiment, the compounds are screened againstcultured WR21 cells (derived from line 69-2 wap-ras mice) for inhibitionof proliferation and/or for altered cellular morphology, in particularfor microtubule compaction. In vivo screening of positive-testingcompounds can then be performed using nude mice bearing the WR21 tumorcells. Detailed protocols for this screening method are described byPorter (1995) Lab. Anim. Sci., 45(2):145-150.

Other methods of screening compounds for desired activity are well knownto those of skill in the art. Typically such assays involve assays forinhibition of microtubule assembly and/or disassembly. Assays formicrotubule assembly are described, for example, by Gaskin et al. (1974)J. Molec. Biol., 89: 737-758. U.S. Pat. No. 5,569,720 also provides invitro and in vivo assays for compounds with paclitaxel-like activity.

Methods for the safe and effective administration of the above-mentionedmicrotubule affecting agents are known to those skilled in the art. Inaddition, their administration is described in the standard literature.For example, the administration of many of the chemotherapeutic agentsis described in the “Physicians' Desk Reference” (PDR), e.g., 1996edition (Medical Economics Company, Montvale, N.J. 07645-1742, USA); thedisclosure of which is incorporated herein by reference thereto.

The amount and frequency of administration of the compounds of formulaIA and the chemotherapeutic agents and/or radiation therapy will beregulated according to the judgment of the attending clinician(physician) considering such factors as age, condition and size of thepatient as well as severity of the disease being treated. A dosageregimen of the compound of formula IA can be oral administration of from10 mg to 2000 mg/day, preferably 10 to 1000 mg/day, more preferably 50to 600 mg/day, in two to four (preferably two) divided doses, to blocktumor growth. Intermittant therapy (e.g., one week out of three weeks orthree out of four weeks) may also be used.

The chemotherapeutic agent and/or radiation therapy can be administeredaccording to therapeutic protocols well known in the art. It will beapparent to those skilled in the art that the administration of thechemotherapeutic agent and/or radiation therapy can be varied dependingon the disease being treated and the known effects of thechemotherapeutic agent and/or radiation therapy on that disease. Also,in accordance with the knowledge of the skilled clinician, thetherapeutic protocols (e.g., dosage amounts and times of administration)can be varied in view of the observed effects of the administeredtherapeutic agents (i.e., antineoplastic agent or radiation) on thepatient, and in view of the observed responses of the disease to theadministered therapeutic agents.

In the methods of this invention, a compound of formula IA isadministered concurrently or sequentially with a chemotherapeutic agentand/or radiation. Thus, it is not necessary that, for example, thechemotherapeutic agent and the compound of formula IA, or the radiationand the compound of formula IA, should be administered simultaneously oressentially simultaneously. The advantage of a simultaneous oressentially simultaneous administration is well within the determinationof the skilled clinician.

Also, in general, the compound of formula IA and the chemotherapeuticagent do not have to be administered in the same pharmaceuticalcomposition, and may, because of different physical and chemicalcharacteristics, have to be administered by different routes. Forexample, the compound of formula IA may be administered orally togenerate and maintain good blood levels thereof, while thechemotherapeutic agent may be administered intravenously. Thedetermination of the mode of administration and the advisability ofadministration, where possible, in the same pharmaceutical composition,is well within the knowledge of the skilled clinician. The initialadministration can be made according to established protocols known inthe art, and then, based upon the observed effects, the dosage, modes ofadministration and times of administration can be modified by theskilled clinician.

The particular choice of a compound of formula IA, and chemo-therapeuticagent and/or radiation will depend upon the diagnosis of the attendingphysicians and their judgement of the condition of the patient and theappropriate treatment protocol.

The compound of formula IA, and chemotherapeutic agent and/or radiationmay be administered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the proliferative disease, the condition ofthe patient, and the actual choice of chemotherapeutic agent and/orradiation to be administered in conjunction (i.e., within a singletreatment protocol) with the compound of formula or IA.

If the compound of formula IA, and the chemotherapeutic agent and/orradiation are not administered simultaneously or essentiallysimultaneously, then the initial order of administration of the compoundof formula IA, and the chemotherapeutic agent and/or radiation, may notbe important. Thus, the compound of formula IA may be administeredfirst, followed by the administration of the chemotherapeutic agentand/or radiation; or the chemotherapeutic agent and/or radiation may beadministered first, followed by the administration of the compound offormula IA . This alternate administration may be repeated during asingle treatment protocol. The determination of the order ofadministration, and the number of repetitions of administration of eachtherapeutic agent during a treatment protocol, is well within theknowledge of the skilled physician after evaluation of the disease beingtreated and the condition of the patient.

For example, the chemotherapeutic agent and/or radiation may beadministered first, especially if it is a cytotoxic agent, and then thetreatment continued with the administration of the compound of formulaIA followed, where determined advantageous, by the administration of thechemotherapeutic agent and/or radiation, and so on until the treatmentprotocol is complete.

Thus, in accordance with experience and knowledge, the practicingphysician can modify each protocol for the administration of a component(therapeutic agent—i.e., the compound of formula IA, chemotherapeuticagent or radiation) of the treatment according to the individualpatient's needs, as the treatment proceeds.

The attending clinician, in judging whether treatment is effective atthe dosage administered, will consider the general well-being of thepatient as well as more definite signs such as relief of disease-relatedsymptoms, inhibition of tumor growth, actual shrinkage of the tumor, orinhibition of metastasis. Size of the tumor can be measured by standardmethods such as radio-logical studies, e.g., CAT or MRI scan, andsuccessive measurements can be used to judge whether or not growth ofthe tumor has been retarded or even reversed. Relief of disease-relatedsymptoms such as pain, and improvement in overall condition can also beused to help judge effectiveness of treatment.

BIOLOGICAL EXAMPLES

The compounds of the present invention are useful in the treatment ofCXC-chemokine mediated conditions and diseases. This utility ismanifested in their ability to inhibit IL-8 and GRO-α chemokine asdemonstrated by the following in vitro assays.

Receptor Binding Assays:

CXCR1 SPA Assay

For each well of a 96 well plate, a reaction mixture of 10 μg hCXCR1-CHOoverexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads(Amersham) in 100 μl was prepared in CXCR1 assay buffer (25 mM HEPES, pH7.8, 2 mM CaCl₂, 1 mM MgCl₂, 125 mM NaCl, 0.1% BSA) (Sigma). A 0.4 nMstock of ligand, [125I]-IL-8 (NEN) was prepared in the CXCR1 assaybuffer. 20× stock solutions of test compounds were prepared in DMSO(Sigma). A 6× stock solution of IL-8 (R&D) was prepared in CXCR2 assaybuffer. The above solutions were added to a 96-well assay plate(PerkinElmer) as follows: 10 μl test compound or DMSO, 40 μl CXCR1 assaybuffer or IL-8 stock, 100 μl of reaction mixture, 50 μl of ligand stock(Final [Ligand]=0.1 nM). The assay plates were shaken for 5 minutes onplate shaker, then incubated for 8 hours before cpm/well were determinedin Microbeta Trilux counter (PerkinElmer). % Inhibition of Totalbinding-NSB (250 nM IL-8) was determined for IC₅₀ values.

Alternative CXCR1 SPA Assay

Protocol Using CXCR1-Expressing Membranes from Biosignal Packard

For each 50 μl reaction, a working stock of 0.25 μg/μl hCXCR1-CHOover-expressing membranes with a specific activity of 0.05 pmol/mg(Biosignal Packard) and 25 μg/μl WGA-SPA beads (Perkin Elmer LifeSciences) was prepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 0.1mM CaCl₂, 1 mM MgCl₂, 100 mM NaCl) (Sigma). This mixture was incubatedon ice for 30 minutes and then centrifuged at 2500 rpm for 5 minutes.The beads and membranes were resuspended in CXCR1 assay buffer to thesame concentrations as in the original mixture. A 0.125 nM stock ofligand, [¹²⁵I]-IL-8 (Perkin Elmer Life Sciences), was prepared in theCXCR1 assay buffer. Test compounds were first serially diluted byhalf-logs in DMSO (Sigma) and then diluted 20-fold in CXCR1 assaybuffer. The above solutions were added to a Corning NBS (non-bindingsurface) 96-well assay plate as follows: 20 μl test compound or 5% DMSO(final [DMSO]=2%), 20 μl of membranes and SPA bead mixture (Final[membrane]=5 μg/reaction; Final [SPA bead]=500 μg/reaction), 10 μl ofligand stock (Final [¹²⁵I-IL-8]=0.025 nM). The assay plates wereincubated for 4 hours before cpm/well were determined in a MicrobetaTrilux counter (Perkin Elmer Life Sciences). IC₅₀ values were quantifiedusing nonlinear regression analysis in GraphPad Prism.

Alternative CXCR1 SPA Assay

Protocol Using CXCR1-expressing Membranes from Euroscreen

For each 50 μl reaction, a working stock of 0.025 μg/μl hCXCR1-CHOover-expressing membranes with a specific activity of 3.47 pmol/mg(Euroscreen) and 5 μg/μl WGA-SPA beads (Perkin Elmer Life Sciences) wasprepared in CXCR1 assay buffer (25 mM HEPES, pH 7.8, 2.0 mM CaCl₂, 1 mMMgCl₂, 125 mM NaCl) (Sigma). This mixture was incubated on ice for 5minutes. A 0.125 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer LifeSciences), was prepared in the CXCR1 assay buffer. Test compounds werefirst serially diluted by half-logs in DMSO (Sigma) and then diluted13.3-fold in CXCR1 assay buffer. The above solutions were added to aCorning NBS (non-binding surface) 96-well assay plate as follows: 20 μltest compound or 7.5% DMSO (final [DMSO]=3%), 20 μl of membranes and SPAbead mixture (Final [membrane]=0.5 μg/reaction; Final [SPA bead]=100μg/reaction), 10 μl of ligand stock (Final [¹²⁵I-IL-8]=0.025 nM). Theassay plates were incubated for 4 hours before cpm/well were determinedin a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ valueswere quantified using nonlinear regression analysis in GraphPad Prism.

For the CXCR1 assay, the compounds of Examples 1 to 6 had a K_(i) withinthe range of 345 nM to 25 μM. The compound of Example 6 had a K_(i) of345 nM.

CXCR2 SPA Assay

For each well of a 96 well plate, a reaction mixture of 4 μg hCXCR2-CHOoverexpressing membranes (Biosignal) and 200 μg/well WGA-SPA beads(Amersham) in 100 μl was prepared in CXCR2 assay buffer (25 mM HEPES, pH7.4, 2 mM CaCl₂, 1 mM MgCl₂). A 0.4 nM stock of ligand, [125I]-IL-8(NEN), was prepared in the CXCR2 assay buffer. 20× stock solutions oftest compounds were prepared in DMSO (Sigma). A 6× stock solution ofGRO-α (R&D) was prepared in CXCR2 assay buffer. The above solutions wereadded to a 96-well assay plate (PerkinElmer or Corning) as follows: 10μl test compound or DMSO, 40 ul CXCR2 assay buffer or GRO-α stock, 100μl of reaction mixture, 50 μl of ligand stock (Final [Ligand]=0.1 nM).When 40× stock solutions of test compounds in DMSO were prepared, thenthe above protocol was used except instead 5 μl test compound or DMSOand 45 μl CXCR2 assay buffer were used. The assay plates were shaken for5 minutes on a plate shaker, then incubated for 2-8 hours beforecpm/well were determined in Microbeta Trilux counter (PerkinElmer). %Inhibition of total binding minus non-specific binding (250 nM Gro-α or50 μM antagonist) was determined and IC50 values calculated. Compoundsof this invention had an IC₅₀ of <5 μM.

Alternative CXCR2 SPA Assay

Protocol Using the CXCR2 50 μl Assay

For each 50 μl reaction, a working stock of 0.031 μg/μl hCXCR2-CHOover-expressing membranes with a specific activity of 0.4 pmol/mg(Biosignal Packard) and 2.5 μg/μl WGA-SPA beads (Perkin Elmer LifeSciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0mM CaCl₂, 1 mM MgCl₂) (Sigma). This mixture was incubated on ice for 5minutes. A 0.50 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer LifeSciences), was prepared in the CXCR2 assay buffer. Test compounds werefirst serially diluted by half-logs in DMSO (Sigma) and then diluted13.3-fold in CXCR2 assay buffer. The above solutions were added to aCorning NBS (non-binding surface) 96-well assay plate as follows: 20 μltest compound or 7.5% DMSO (final [DMSO]=3%), 20 μl of membranes and SPAbead mixture (final [membrane]=0.625 μg/reaction; final [SPA bead]=50μg/reaction), 10 μl of ligand stock (final [¹²⁵I-IL-8]=0.10 nM). Theassay plates were incubated for 2 hours before cpm/well were determinedin a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ valueswere quantified using nonlinear regression analysis in GraphPad Prism.

Alternative CXCR2 SPA Assay

Protocol Using the CXCR2 200 μl Assay

For each 200 μl reaction, a working stock of 0.02 μg/μl hCXCR2-CHOover-expressing membranes with a specific activity of 0.6 pmol/mg(Biosignal Packard) and 2 μg/μl WGA-SPA beads (Perkin Elmer LifeSciences) was prepared in CXCR2 assay buffer (25 mM HEPES, pH 7.4, 2.0mM CaCl₂, 1 mM MgCl₂) (Sigma). This mixture was incubated on ice for 5minutes. A 0.40 nM stock of ligand, [¹²⁵I]-IL-8 (Perkin Elmer LifeSciences), was prepared in the CXCR2 assay buffer. Test compounds werefirst serially diluted by half-logs in DMSO (Sigma) and then diluted20-fold in CXCR2 assay buffer. The above solutions were added to aCorning NBS (non-binding surface) 96-well assay plate as follows: 50 μltest compound or 10% DMSO (final [DMSO]=2.5%), 100 μl of membranes andSPA bead mixture (final [membrane]=2 μg/reaction; final [SPA bead]=200μg/reaction), 50 μl of ligand stock (final [¹²⁵I-IL-8]=0.10 nM). Theassay plates were incubated for 2 hours before cpm/well were determinedin a Microbeta Trilux counter (Perkin Elmer Life Sciences). IC₅₀ valueswere quantified using nonlinear regression analysis in GraphPad Prism.

For the CXCR2 assay, the compounds of Examples 1 to 6 had a K_(i) withinthe range of 7.6 nM to 51 nM. The compound of Example 2 had a K_(i) of7.6 nM, and the compound of Example 6 had a K_(i) of 19 nM.

Calcium Fluorescence Assay (FLIPR)

HEK 293 cells stably transfected with hCXCR2 and Gαι/q were plated at10,000 cells per well in a Poly-D-Lysine Black/Clear plate (BectonDickinson) and incubated 48 hours at 5% CO₂, 37° C. The cultures werethen incubated with 4 mM fluo-4, AM (Molecular Probes) in Dye LoadingBuffer (1% FBS, HBSS w. Ca & Mg, 20 mM HEPES (Cellgro), 2.5 mMProbenicid (Sigma) for 1 hour. The cultures were washed with wash buffer(HBSS w Ca, & Mg, 20 mM HEPES, Probenicid (2.5 mM)) three times, then100 μl/well wash buffer was added.

During incubation, compounds were prepared as 4× stocks in 0.4% DMSO(Sigma) and wash buffer and added to their respective wells in the firstaddition plate. IL-8 or GRO-α (R&D Systems) concentrations were prepared4× in wash buffer+0.1% BSA and added to their respective wells in secondaddition plate.

Culture plate and both addition plates were then placed in the FLIPRimaging system to determine change in calcium fluorescence upon additionof compound and then ligand. Briefly, 50 μl of compound solutions orDMSO solution was added to respective wells and change in calciumfluorescence measured by the FLIPR for 1 minute. After a 3 minuteincubation within the instrument, 50 μl of ligand was then added and thechange in calcium fluorescence measured by the FLIPR instrument for 1minute. The area under each stimulation curve was determined and valuesused to determine % Stimulation by compound (agonist) and % Inhibitionof Total Calcium response to ligand (0.3 nM IL-8 or GRO-α) for IC50values of the test compounds.

Chemotaxis Assays for 293-CXCR2

A chemotaxis assay is setup using Fluorblok inserts (Falcon) for293-CXCR2 cells (HEK-293 cells overexpressing human CXCR2). The standardprotocol used at present is as follows:

-   1. Inserts are coated with collagenIV (2 ug/ml) for 2 hrs at 37° C.-   2. The collagen is removed and inserts are allowed to air dry    overnight.-   3. Cells are labeled with 10 uM calcein AM (Molecular Probes) for 2    hrs. Labeling is done in complete media with 2% FBS.-   4. Dilutions of compound are made in minimal media (0.1% BSA) and    placed inside the insert which is positioned inside the well of a 24    well plate. Within the well is IL-8 at a concentration of 0.25 nM in    minimal media. Cells are washed and resuspended in minimal media and    placed inside the insert at a concentration of 50,000 cells per    insert.-   5. Plate is incubated for 2 hrs and inserts are removed and placed    in a new 24 well. Fluorescence is detected at excitation=485 nM and    emission=530 nM.    Cytotoxicity Assays

A cytotoxicity assay for CXCR2 compounds is conducted on 293-CXCR2cells. Concentrations of compounds are tested for toxicity at highconcentrations to determine if they may be used for further evaluationin binding and cell based assays. The protocol is as follows:

-   1. 293-CXCR2 cells are plated overnight at a concentration of 5000    cells per well in complete media.-   2. Dilutions of compound are made in minimal media w/0.1% BSA.    Complete media is poured off and the dilutions of compound are    added. Plates are incubated for 4, 24 and 48 hrs. Cells are labeled    with 10 uM calcein AM for 15 minutes to determine cell viability.    Detection method is the same as above.    Soft Agar Assay

10,000 SKMEL-5 cells/well are placed in a mixture of 1.2% agar andcomplete media with various dilutions of compound. Final concentrationof agar is 0.6%. After 21 days viable cell colonies are stained with asolution of MTT (1 mg/ml in PBS). Plates are then scanned to determinecolony number and size. IC₅₀ is determined by comparing total area vs.compound concentration.

CCR7 Membrane Preparation.

Ba/F3-CCR7 membranes were prepared as previously described (Hipkin etal., J. Biol. Chem., 272, 1997, 13869-76). Cells were pelleted bycentrifugation, incubated in homogenization buffer (10 mM Tris-HCl, 5 mMEDTA, 3 mM EGTA, pH 7.6) and 1 μM PMSF for 30 min. on ice. The cellswere then lysed with a Dounce homogenizer using stirrer type RZR3polytron homogenizer (Caframo, Wiarton, Ont.) with 12 strokes at 900RPM. The intact cells and nuclei were removed by centrifugation at 500×gfor 5 min. The cell membranes in the supernatant were then pelleted bycentrifugation at 100,000×g for 30 min. The membranes were thenresuspended in glygly buffer (20 mM glycylglycine, 1 mM MgCl₂, 250 mMsucrose, pH 7.2), aliquoted, quick frozen and stored at −80° C.

CCR7 [³⁵S]GTPγS Exchange Assay.

The exchange of guanosine 5′-[γ-³⁵S]triphospate ([³⁵S]GTPγS,triethylammonium salt; specific activity=1250 Ci/mmol; NEN Boston,Mass.) was measured using a scintillation proximity assay (SPA) aspreviously described (Cox, et. al., Mol. Pharmacol., 59, 2001, 707-15).For each assay point, 2 μg of membrane was preincubated for 30 min atroom temperature with 200 μg wheat germ agglutinin-coated SPA beads(WGA-SPA; Amersham, Arlington Heights, Ill.) in SPA binding buffer (50mM HEPES, 10 mM MgCl₂, 1 mM EDTA, 100 mM NaCl, 0.1% BSA, pH 7.6). Thebeads and membranes were transferred to a 96-well Isoplate (Wallac,Gaithersburg, Md.) and incubated with 10 μM guanosine 5′-diphosphate(GDP) in the presence or absence of 2 nM MIP-3β and/or compounds for 60min at room temperature. The incubation continued for another 60 min.following the addition of 0.1 nM [³⁵S]GTPγS. Membrane-bound [³⁵S]GTPγSwas measured using a 1450 Microbeta Trilux counter (Wallac,Gaithersburg, Md.).

The compound of Example 162 had an EC₅₀ of 9.5 μM.

Rat Carrageenan-Induced Thermal Hyperalgesia

Male Sprague-Dawley rats (Charles River Laboratories; 150-200 gm) can bemaintained under normal housing and lighting conditions, with food andwater supplied ad libitum. Each animal can be tested for its baselinepaw withdrawal response to a heat source by placement of the animal intoa plantar testing unit (Ugo Basile, Italy), in which a light source ismoved under its paw and the time of withdrawal is measured. The animalscan then be dosed orally with a compound of this invention, and then canbe injected intraplantarly with 2-3 mg lambda carrageenan (FMC Colloids)in 100 ul of saline while under isofurane anesthesia. Three hours later,the animals can be re-measured for their withdrawal response to the heatsource. Plantar tissue can also be analyzed for myeloperoxidase levelsas a surrogate for neutrophil infiltration.

General Process Scheme

A general procedure for the preparation of compounds of formula IA is asfollows:

Step A

Following a similar procedure outlined in J. Org. Chem, V 48, No: 6,1983, P 763-767, but using the R⁵⁰CH₂SO₂NH₂ indicated, the desiredisothiazoledioxide intermediate could be prepared.

Step B

Compounds of this invention are prepared by condensing an amine (eitherA-NH₂ or B-NH₂) with the known isothiazoledioxide prepared according tothe literature to give the isothiazoledioxide intermediate. Subsequentcondensation of this intermediate with the commercially available orprepared amine (either A-NH₂ or B-NH₂) provides the desired chemokineantagonist. For Examples where R⁵⁰═C(O)OR¹³, saponification with heatingand subsequent acidification provides the desired R⁵⁰═H compounds.

The invention disclosed herein is exemplified by the followingpreparations and examples which should not be construed to limit thescope of the disclosure. Alternative mechanistic pathways and analogousstructures may be apparent to those skilled in the art.

Preparative Example 1

3-Nitrosalicylic acid (500 mg, 2.7 mmol), DCC (563 mg) and ethyl acetate(10 mL) were combined and stirred for 10 min.(R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and the resultingsuspension was stirred at room temperature overnight. The solid wasfiltered and the filtrate washed with 1N NaOH. The aqueous phase wasacidified and extracted with EtOAc. The resulting organic phase wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the residue by preparative plate chromatography (silicagel, 5% MeOH/CH₂Cl₂ saturated with ACOH) gave the product (338 mg, 46%,MH⁺=267).

Preparative Example 2

Step A

3-Nitrosalicylic acid (9.2 g), bromotripyrrolidinophosphoniumhexafluorophosphate (PyBroP, 23 g) and N,N-diisopropylethylamine (DIEA,26 mL) in anhydrous CH₂Cl₂ (125 mL) were combined and stirred at 25° C.for 30 min. (R) -(+)-3-pyrrolidinol (8.7 g) in CH₂Cl₂ (25 mL) was addedover 25 min and the resulting suspension was stirred at room temperatureovernight. The mixture was extracted with 1M NaOH (aq) and the organicphase was discarded. The aqueous phase was acidified with 1M HCl (aq),extracted with EtOAc, dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo to afford the crude product (7 g) which was usedwithout further purification.

Step B

The crude product from Step A above was stirred with 10% Pd/C (0.7 g) inMeOH (100 mL) under a hydrogen gas atmosphere overnight. The reactionmixture was filtered through celite, the filtrate concentrated in vacuo,and the resulting residue purified by column chromatography (silica gel,10% MeOH/CH₂Cl₂ saturated with NH₄OH) to give the product (2.5 g, 41%,MH+=223).

Preparative Example 2.1

To N-BOC-3-(amino)piperidine (0.5 g) dissolved in CH₂Cl₂ (10 mL) wasadded benzylisocyanate (3 mmol). After stirring for 2 hrs, aminescavenger resin (1.9 mmol) was added and the mixture was stirredovernight, filtered, the resin back-washed with CH₂Cl₂ and methanol, andthe organics concentrated in vacuo. Stirring of the crude material in 4NHCl/dioxane (40 mL) for 2.5 hrs before concentrating in vacuo gave thetitle compound (41%, MH+=369).

Preparative Example 2.2-2.6

Following the procedures set forth in Preparative Example 2.1 but usingthe isocyanate (or chloroformate) indicated in the Table below, theamines were obtained and used without further purification.

Prep Ex. Amine Isocyanate Amine 2.2

2.3

2.4

2.5

2.6

Preparative Example 2.7

To N-BOC-3-(amino)piperidine (5 mmol) dissolved in CH₂Cl₂ (30 mL) wasadded trifluoromethanesulfonic anhydride (5 mmol) and the mixture wasstirred overnight. The mixture was concentrated in vacuo, diluted withCH₂Cl₂ (10 mL) and treated with trifluoroacetic acid (10 mL). Afterstirring for 2 hr, the mixture was concentrated in vacuo to give thetitle compound (43%, MH+=233.1).

Preparative Example 2.8

Step A

3-Nitrosalicylic acid (5 mmol) and N-hydroxysuccinimide (5 mmol) wereadded to a solution of 2% DMF/CH₂Cl₂, followed by DCC (5 mmol). Afterstirring for 2 hr, the mixture was filtered and concentrated in vacuoand the residue used directly in Step B.

Step B

The product from Step A above was suspended in DMF and to this was addedmorpholino-2-carboxylic acid HCl (5 mmol) in CH₂Cl₂ (10 mL)/DMF (5 mL)and diisopropylethylamine (10 mmol). The mixture was stirred overnight,filtered, basified with 1 N NaOH (50 mL), washed with CH₂Cl₂, acidifiedwith 5N HCl and extracted with EtOAc. The organic phase was dried overNa₂SO₄, filtered and concentrated in vacuo to give the desired compoundwhich was used directly in Step C (MH+=296).

Step C

Following a similar procedure as in Preparative Example 2 Step B, butusing the product from Step B above, the title compound was obtained(23%, MH+=267).

Preparative Example 2.9

Step A

2-Piperazinecarboxylic acid and 2-chloro-1,3-pyrimidine were stirredwith triethylamine and MeOH. After stirring overnight at reflux, themixture was filtered and concentrated in vacuo to give the desiredcompound which was used directly in Step B (MH+=209).

Step B

Following a similar procedure as Preparative Example 2.8, Step B exceptusing the product from Preparative Example 2.9 Step A above, the desiredcompound was obtained (41%, MH+=374).

Step C

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step B above, the desired compound was obtained(99%, MH+=344).

Preparative Example 2.10

Step A

Following a similar procedure as Preparative Example 2.8, Step A exceptusing 3-nitrobenzbic acid, the desired compound was obtained and useddirectly in Step B.

Step B

Following a similar procedure as Preparative Example 2.8, Step B exceptusing the products from Preparative Example 2.9, Step A and PreparativeExample 2.10, Step A, the desired compound was obtained (86%).

Step C

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step B above, the desired compound was obtained(67%, MH+=331).

Preparative Example 2.11

Step A

N-Benzylpiperidone (2 g, HCl salt, hydrate) was stirred with THF (20mL), concentrated to dryness, and placed under high vac. The residue wasdiluted in THF (20 mL), and methyllithium was added (2.5 eq of 1.6N inEt₂O) via syringe. After stirring for 3 hr, the mixture was concentratedin vacuo, diluted with water, extracted with CH₂Cl₂, and dried overNa₂SO₄. Filtration and concentrating in vacuo gave the desired product(50%, MH+=205).

Step B

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step A above, the title compound was obtained(95%, MH+=116).

Preparative Example 2.12

Step A

To N-benzyl-N-methylamine (20 mmol) dissolved in acetone (50 mL) wasadded concentrated HCl (20 mmol), paraformaldehyde (30 mmol) and2-propanol (2 mL). After stirring at reflux overnight, the mixture wasconcentrated in vacuo, diluted with water, basified to pH 14 andextracted with ether. The organic phase was dried over Na₂SO₄, filteredand concentrated in vacuo to give the desired product (98%) which wasused directly in Step B.

Step B

The product from Step A above (500 mg) was dissolved in MeOH (20 mL) andto this was added NaBH₄ (50 mg). After stirring for 10 min, the solutionwas concentrated in vacuo to give the desired compound which was useddirectly in Step C without purification.

Step C

The product from Step B above was diluted with MeOH (20 mL) and to thiswas added AcOH (0.1 mL), a catalytic amount of Pd/C (10%) and themixture stirred under H₂ atmosphere (balloon) overnight. The mixture wasfiltered, 4N HCl in dioxane (1 mL) was added, and the mixture wasconcentrated in vacuo to give the desired compound that was useddirectly without purification.

Preparative Example 2.13

Step A

Following a similar procedure as Preparative Example 2, Step A exceptusing methyl glycinate, the desired ester was obtained. The mixture waspoured into 200 mL of 1 N NaOH, then extracted with dichloromethane. ThepH was adjusted to 1 and NaCl was added until saturation. After severalhours, the resulting precipitate was filtered and washed with cold waterto give the desired product (42%).

Step B

Following a similar procedure as in Preparative Example 2 Step B, butusing the product from Step A above, the title compound was obtained(95%).

Preparative Example 2.14

Step A

Following a similar procedure as in Preparative Example 2.13, Step Aexcept using methyl N-methylglycinate, the desired product was obtained(18%).

Step B

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step A above, the title compound was obtained(95%, MH+=225).

Preparative Example 2.16

The above n-oxide (2 g) was combined with H₂NMe/H₂O (15 cm³) and heatedto 140° C. overnight. Potassium carbonate (1.3 g) added and the mixtureconcentrated in vacuo. Extraction with EtOH and concentration of thefiltrate in vacuo gave 1.56 g of crude amine (MH+=125).

Preparative Example 3-10.50

Following the procedures set forth in Preparative Examples 1-2 but usingthe carboxylic acid, amine, and coupling agent [DCC (Prep. Ex. 1) orPyBrop (Prep. Ex. 2)] listed in the Table below, the indicated amideproducts were obtained and used without further purification.

Product 1. Coupling Agent Prep 2. % yield Ex. Carboxylic acid Amine 3.MH⁺ 3

1. PyBrop 2. 87, 86 3. 181 4

1. PyBroP 2. 49 3. 209 5

NH₃

1. PyBroP 2. 95 3. 153 6

—NH₂

1. PyBroP 2. 83 3. 167 7

1. PyBroP 2. 76 3. 223 8

1. PyBroP 2. 65, 53 3. 209 9

1. PyBroP 2. 59, 69 3. 207 10

1. PyBroP 2. 49, 86 3. 237 10.1

1. PyBroP 2. 30, 88 3. 193 10.2

1. PyBroP 2. 26, 87 3. 195 10.3

1. PyBroP 2. 38 3. 209 10.4

1. PyBroP 2. 29 3. 209 10.5

1. PyBroP 2. 38 3. 223 10.6

1. PyBroP 2. 32, 99 3. 367.9 10.7

1. PyBroP 2. 35, 99 3. 237 10.8

1. DCC 2. 30, 99 3. 269 10.9

1. PyBroP 2. 58, 95 3. 233.1 10.10

1. PyBroP 2. 42, 95 3. 238.9 10.13

1. PyBroP 2. 51, 95 3. 307 10.14

1. PyBroP 2. 55 3. 347 10.15

1. PyBroP 2. 41 3. 369.1 10.16

1. PyBroP 2. 56 3. 354.9 10.17

1. PyBroP 2. 56 3. 308 10.18

1. PyBroP 2. 10, 95 3. 252.9 10.19

1. PyBroP 2. 42, 95 3. 249 10.20

1. PyBroP 2. 15, 95 3. 264.9 10.21

1. PyBroP 2. 64, 95 3. 273 10.22

1. PyBroP 2. 45, 95 3. 273 10.23

1. PyBroP 2. 44, 95 3. 281 10.24

1. PyBroP 2. 41, 95 3. 281.1 10.25

1. PyBroP 2. 48, 95 3. 257 10.26

1. DCC 2. 15, 99 3. 235 10.28

1. PyBroP 2. 52, 95 3. 237.1 10.29

1. PyBroP 2. 31, 95 3. 259.1 10.30

1. PyBroP 2. 54, 95 3. 250.9 10.31

1. PyBroP 2. 64, 95 3. 210.9 10.32

1. PyBroP 2. 47, 95 3. 197 10.33

1. PyBroP 2. 47, 95 3. 273 10.34

1. PyBroP 2. 51, 95 3. 237.1 10.35

1. PyBroP 2. 60, 90 3. 224 10.36

1. PyBroP 2. 65, 99 3. 252 10.37

1. PyBroP 2. 58, 99 3. 239 10.38

1. PyBroP 2. 35, 99 3. 221.1 10.39

1. PyBroP 2. 42, 99 3. 235.2 10.40

1. DCC 2. 32, 99 3. 293.1 10.41

1. PyBroP 2. 45, 99 3. 223.1 10.42

1. PyBroP 2. 55, 81 3. 251.1 10.43

1. PyBroP 2. 68, 66 3. 224.9 10.44

1. PyBroP 2. 68, 66 3. 241.1 10.45

1. PyBroP 2. 44, 40 3. 295 10.46

1. DCC 2. 37, 81 3. 265 10.47

1. PyBroP 2. 71, 95 3. 293.1 10.48

1. PyBroP 2. 35, 99 3. 220.9 10.49

1. DCC 2. 16, 99 3. 209.0 10.50

1. DCC 2. 18, 99 3. 264.0

Preparative Example 10.55 Alternative Procedure for Preparative Example3

To the nitrosalicylic acid (3 g) dissolved dichloromethane (150 mL) atroom temperature was added oxalyl chloride (4.3 mL) and DMF (0.01 eq.).After stirring for one day the mixture was concentrated in a vacuum togive a semi solid which was used directly in step B.

To the material from step A diluted in dichloromethane (50 mL) andcooled to 0° C. was added dimethyl amine in THF (2N solution, 24.6 mL)and triethylamine (4 eq.). After stirring for 24 hours at roomtemperature the mixture was concentrated in vacuo, diluted with 1Msodium hydroxide (30 mL) and after a half hour was washed withdichloromethane. The aqueous phase was acidified with 6M HCl (aq),extracted with dichloromethane and the organic phase was washed withwater, dried over Na₂SO₄ and concentrated to give the title compound(3.2 g, 93%).

A mixture of the product from step B above (6 g), 10% Pd/C (0.6 g), andEtOH (80 mL) was stirred in a parr shaker under hydrogen (40 psi) atroom temperature for 2 days. Filtration through celite and concentrationin vacuo afforded the title product (5.1 g, 99%, MH⁺=181).

Preparative Example 11

Step A

Following a similar procedure as in Preparative Example 1 except usingdimethylamine (2M in THF, 33 mL) and 5-methylsalicylic acid (5 g), thedesired product was prepared (6.5 g).

Step B

Nitric acid (0.8 mL) in H₂SO₄ was added to a cooled (−20° C.) suspensionof the product from Step A above (3 g) in H₂SO₄ (25 mL). The mixture wastreated with 50% NaOH (aq) dropwise, extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give the productas a crude solid (2.1 g, 44%, MH⁺=225).

Step C

The product was prepared in the same manner as described in Step B ofPreparative Example 2 (0.7 g, 99%, MH⁺=195).

Preparative Example 11.1

Step A

The above amine was reacted with the acid using the procedure set forthin Preparative Example 2, Step A to yield the desired amide (54%).

Step B

Na₂S₂O₄ (1.22 g) was dissolved in water (4 ml) followed by the additionof NH₃/H₂O (300 ul). The solution ws then added to the product from StepA (200 mg) in dioxane (4 ml) and stirred for 30 min. The crude materialwas purified via flash column chromatography (CH₂Cl₂/MeOH, 20:1) to give100 mg of product (56%, MH+=251).

Preparative Example 11.2

Following the procedures set forth in Preparative Example 11.1, Steps Aand B, but using N-methylmethoxylamine, the title compound was obtained(86%, MH+=181).

Preparative Example 11.10

Step A

Following the procedure set forth in Preparative Example 1, but usingN-hydroxysuccinimide and 2% DMF in CH₂Cl₂, the desired amide wasobtained (33%, MH+=297).

Step B

Following the procedure set forth in Preparative Example 2, Step B, theamine was prepared (99%, MH+=267).

Preparative Example 11.11-11.18

Following the procedures set forth in Preparative Examples 11.11 butusing the carboxylic acid, amine, and coupling agent DCC indicated, theindicated amide products were obtained and used without furtherpurification.

Prep Carboxylic 1. % Yield Ex. acid Amine Product 2. MH⁺ 11.11

1. 45.92 2. 310.0 11.12

1. 45.95 2. 247.2 11.13

1. 85.85 2. 251.1 11.14

1. 99.92 2. 211.1 11.15

1. 48.84 2. 265 11.16

1. 78.91 2. 238.1 11.17

1. 67.90 2. 265.1 11.18

1. 28.99 2. 267

Preparative Example 12

Step A

Following a similar procedure as described in Preparative Example 2 StepA except using dimethylamine in place of R-(+)-3-pyrrolidinol, thedesired product was prepared.

Step B

The product from step A above (8 g) was combined with iodine (9.7 g),silver sulfate (11.9 g), EtOH (200 mL) and water (20 mL) and stirredovernight. Filtration, concentration of the filtrate, re-dissolution inCH₂Cl₂ and washing with 1M HCl (aq) gave an organic solution which wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo to affordthe product (7.3 g, 57%, MH⁺=337).

Step C

The product from Step B above (3.1 g) was combined with DMF(50 mL) andMel (0.6 mL). NaH (60% in mineral oil, 0.4 g) was added portionwise andthe mixture was stirred overnight. Concentration in vacuo afforded aresidue which was diluted with CH₂Cl₂, washed with 1M NaOH (aq), driedover anhydrous MgSO₄, filtered and concentrated in vacuo. Purificationthrough a silica gel column (EtOAc/Hex, 1:1) gave the desired compound(1.3 g, 41%, MH⁺=351).

Step D

The product from Step D above (200 mg), Zn(CN)₂ (132 mg), Pd(PPh₃)₄ (130mg) and DMF (5 mL) were heated at 80° C. for 48 hrs, then cooled to roomtemperature and diluted with EtOAc and 2M NH₄OH. After shaking well, theorganic extract was dried over anhydrous MgSO₄, filtered, concentratedin vacuo and purified by preparative plate chromatography (Silica,EtOAc/Hex, 1:1) to give the desired compound (62 mg, 44%, MH⁺=250).

Step E

BBr₃ (1.3 mL, 1 M in CH₂Cl₂) was added to a CH₂Cl₂ solution (5 mL) ofthe product from step D above (160 mg) and stirred for 30 min. Themixture was diluted with water, extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo to give the desiredcompound (158 mg, MH⁺=236).

Step F

A mixture of the product from step E above (160 mg), platinum oxide(83%, 19 mg), and EtOH (20 mL) was stirred under hydrogen (25-40 psi)for 1.5 hr. Filtration through celite and concentration in vacuoafforded the product (165 mg, MH⁺=206).

Preparative Example 12.1

Step A

Following a similar procedure as in Preparative Example 2, Step A exceptusing 3-(methylaminomethyl)pyridine and 3-nitrosalicylic acid, thedesired compound was prepared (41%).

Step B

The compound from Step A above (0.3 g) was diluted with chloroform (15mL) and stirred with mCPBA (0.4 g) for 2 hr. Purification by columnchromatography (silica, 10% MeOH/CH₂Cl₂) gave the pyridyl N-oxide (0.32g, 100%, MH⁺=303.9).

Step C

Following a similar procedure as in Preparative Example 11.1, Step B,but using the product from Step B above, the desired compound wasobtained (15%, MH+=274).

Preparative Example 12.2

Step A

3-Nitrosalicylic acid (4 g) in MeOH (100 mL) and concentrated H₂SO₄ (1mL) were stirred at reflux overnight, concentrated in vacuo, dilutedwith CH₂Cl₂, and dried over Na₂SO₄. Purification by columnchromatography (silica, 5% MeOH/CH₂Cl₂) gave the methyl ester (2.8 g,65%).

Step B

Following a similar procedure as in Preparative Example 2, Step B, butusing the product from Step A above, the desired compound was obtained(95%, MH+=167.9).

Preparative Example 12.3

To morpholine-2-carboxilic acid (200 mg) in EtOH (40 mL) at 0° C. wasadded acetyl chloride (3 mL) and the mixture was stirred at refluxovernight. Concentration in vacuo, dilution with CH₂Cl₂ and washing withNaHCO₃ (aq) gave the title compound (99%, MH⁺=160.1).

Preparative Example 12.4

To N-Boc morpholine-2-carboxylic acid (2 g) in THF (5 ml) at 0° C. wasadded a solution of borane.THF complex (1 N, 10.38 ml) and the mixturewas stirred for 30 min at 0° C., and for 2 hr at room temperature. Water(200 ml) was added to the reaction and the mixture extracted withCH₂Cl₂, dried with Na₂SO₄, and concentrated in vacuo to give 490 mg ofproduct (26%). The product was then stirred in 4N HCl/dioxane to givethe amine salt.

Preparative Example 13

Step A

Following a similar procedure as in Preparative Example 1 except usingdimethylamine (2M in THF, 50 mL) and 4-methylsalicylic acid (15 g), thedesired compound was prepared (6.3 g, 35%) .

Step B

The product from Step A above (1.5 g) was combined with iodine (2.1 g),NaHCO₃ (1.1 9), EtOH (40 mL) and water (10 mL) and stirred overnight.Filtration, concentration of the filtrate, re-dissolution in CH₂Cl₂ andwashing with 1M HCl (aq) gave an organic solution which was dried overanhydrous MgSO₄, filtered and concentrated in vacuo. Purification byflash column chromatography (silica gel, 0.5-0.7% MeOH/CH₂Cl₂) gave theproduct (0.5 g, 20%, MH⁺=306).

Step C

Nitric acid (3.8 mL) in AcOH (10 mL) was added to the product from StepB above (0.8 g) and the mixture was stirred for 40 min. The mixture wasdiluted with water and extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to give the product as anorange solid (0.8 g, 92%, MH⁺=351).

Step D

A mixture of the product from step C above (800 mg), 10% Pd/C (100 mg),and EtOH/MeOH (40 mL) was stirred in a parr shaker under hydrogen (45psi) for 1.5 hr. Filtration through celite and concentration in vacuoafforded the title product after purification by preparative platechromatography (Silica, 10% MeOH/CH₂Cl₂, saturated with NH₄OH) to givethe product (92 mg, 22%, MH⁺=195).

Preparative Example 13.1

Step A

Following a similar procedure as in Preparative Example 2, Step A exceptusing dimethylamine (2M in THF, 23 ml) and 5-bromosalicylic acid (5 g),the desired compound was prepared (4.2 g, 75%, MH+=244).

Step B

Nitric acid (10 ml) in AcOH (100 ml) was added to the product from StepA above (2 g) and the mixture was stirred for 20 min. The mixture wasdiluted with water and extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to give the product as ayellow solid (1.9 g, 80%, MH+=289).

Step C

The product from Step B above (1.9 g) was partially dissolved in EtOH(50ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O (5.74 g)was added and stirred at room temperature overnight. The crude reactionwas concentrated in vacuo, diluted with CH₂Cl₂ and washed with NaHCO₃,dried over anhydrous MgSO₄, filtered and concentrated in vacuo to givethe product as a solid (185 mg, 9%, MH+=259).

Preparative Example 13.2

Step A

Following a similar procedure as in Preparative Example 2, Step A,except using dimethylamine (2M in THF, 29 ml) and 5-chlorosalicylic acid(5 g), the desired compound was prepared (4.5 g, 78%, MH+=200).

Step B

Nitric acid (10 ml) in ACOH (100 ml) was added to the product from StepA above (2 g) and the mixture was stirred for 20 min. The mixture wasdiluted with water and extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo to give the product as a solid(2.2 g, 88%, MH+=245).

Step C

The product from Step B above (2.2 g) was partially dissolved in EtOH(50ml). Conc HCl in EtOH (5 ml in 40 ml), followed by SnCl₂.2H₂O (7.01 g)was added and stirred at room temperature overnight. The crude reactionwas concentrated in vacuo, diluted with CH₂Cl₂ and neutralized withNaOH. The entire emulsion was filtered though celite, the layers wereseparated and the organic layer was dried over anhydrous MgSO₄, filteredand concentrated in vacuo to give a solid (540 mg, 22%, MH+=215).

Preparative Example 13.3

Step A

3-Nitrosalicylic acid (10 g), PyBroP (20.52 g), and DIEA (28 ml) inanhydrous CH₂Cl₂ (200 ml) were combined and stirred at room temperaturefor 10 min. Dimethylamine (2M in THF, 55 ml) was added and let thereaction stir over the weekend. The mixture was extracted with 1N NaOH(aq) and the organic phase was discarded. The aqueous phase wasacidified with 1N HCl (aq), extracted with CH₂Cl₂, dried over anhydrousMgSO₄, filtered and concentrated in vacuo. The oil was taken up in etherand a solid crashed out, triterated in ether to give 4.45 g of a solid(39%, MH+=211).

Step B

The product from Step A (2.99 g), K₂CO₃ (9.82 g), and iodomethane (8.84ml) were combined in acetone and heated to reflux overnight. Thereaction was filtered and concentrated in vacuo. The oil was taken up inCH₂Cl₂ and washed with 1N NaOH, dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to give 3.3 g of an oil (99%, MH+=225).

Step C

The crude product from Step B (3.3 g) was stirred with 10% Pd/C (350 mg)in EtOH (50 ml) under a hydrogen gas atmosphere at 20 psi overnight. Thereaction mixture was filtered through celite and the filtrate wasconcentrated in vacuo to give 2.34 g of a solid (85%, MH+=195).

Step D

The product from Step C (469 mg) was dissolved in AcOH (6 ml). 1.95M Br₂in AcOH (1.23 ml) was added dropwise to the reaction and the mixture wasstirred at room temperature for 1 hour. 50% NaOH was added to thereaction at 0° C. and the mixture was extracted with CH₂Cl₂, dried overanhydrous MgSO₄, filtered and concentrated in vacuo. The crude mixturewas purified by preparative plate chromatography (Silica, 5%MeOH/CH₂Cl₂) to give the desired product (298 mg, 23%, MH+=273).

Step E

BBr₃ (2.14 ml, 1M in CH₂Cl₂) was added to a CH₂Cl₂ solution (8 ml) ofthe product from Step D above (290 mg) and stirred overnight. A solidformed and was filtered, taken up in MeOH/CH₂Cl₂ and purified bypreparative plate chromatography (Silica, 5% MeOH/CH₂Cl₂) to give thedesired product (137 mg, 49%, MH+=259).

Preparative Example 13.4

Step A

To the product from Preparative Example 13.3 Step D (200 mg) was addedphenylboronic acid (98 mg), PdCl₂(PPh₃)₂ (51 mg), and Na₂CO₃ (155 mg) inTHF/H₂O (4 ml/1 ml). The solution was heated at 80° C. overnight. EtOAcwas added to reaction and washed with 1N NaOH. The organic layer wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude mixture was purified by preparative plate chromatography (5%MeOH/CH₂Cl₂) to give 128 mg of an oil (65%, MH+=271).

Step B

Following a similar procedure as in Preparative Example 13.3 Step E andusing the product from Step A above, the desired compound was prepared(0.1 g, 69%, MH+=257.1).

Preparative Example 13.5-13.7

Following the procedures set forth in Preparative Example 13.4 but usingthe boronic acid from the Preparative Example indicated in the Tablebelow, the amine products were obtained.

1. Yield (%) Prep Ex. Boronic Acid Product 2. MH⁺ 13.5

1. 15% 2. 258 13.6

1. 32% 2. 325 13.7

1. 18% 2. 325

Preparative Example 13.8

Step A

2-Cyanophenol (500 mg), sodium azide (819 mg), and triethylaminehydrochloride (1.73 g) were combined in anhydrous toluene and heated to99° C. overnight. After the reaction cooled down, product was extractedwith H₂O. Aqueous layer was acidified with conc. HCl dropwise giving aprecipitate, which was filtered to give the product (597 mg, 87%,MH+=163).

Step B

Nitric acid (0.034 ml) in AcOH (5 ml) was added to the product from StepA above (100 mg) in AcOH and the mixture was allowed to stir for 1 hr.CH₂Cl₂ and H₂O were added to reaction. The organic layer was dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give an oil.Trituration in ether gave the product as a solid (12 mg, 9%, MH+=208).

Step C

The product from step C (56 mg) was stirred with 10% Pd/C (20 mg) inEtOH/MeOH (15 ml) under a hydrogen gas atmosphere overnight. Thereaction mixture was filtered through celite, the filtrate wasconcentrated in vacuo to give 29 mg of a solid (62%, MH+=178).

Preparative Example 13.9

The amine was prepared following the procedure disclosed in WO 01/68570,the disclosure of which is incorporated herein by reference thereto.

Preparative Example 13.10

The amine was prepared following the procedure disclosed in WO 01/68570,the disclosure of which is incorporated herein by reference thereto.

Preparative Example 13.11

Step A

Following the procedure described in Preparative Example 88.2, Step A,the ketone was prepared (6.4 g, 36%).

Step B

To a solution of ketone (1 g) and 2-R-methylbenzylamine (0.73 ml) inanhydrous toluene (20 ml) was added 1N TiCl₄ in toluene (3 ml) at roomtemperature for 1.5 hrs. The precipitate was filtered and the filtratewas concentrated in vacuo and purified via flash column chromatography(Hex/EtOAc, 18/1) to give 800 mg of product (71%).

Step C

The imine from above (760 mg) and DBU (800 ul) were stirred withoutsolvent for 4 hr. The crude reaction was concentrated in vacuo andpurified via flash column chromatography (Hex/EtOAc, 8/1) to give 600 mgof product (79%).

Step D

The imine from Step C (560 mg) was dissolved in ether (8 ml). 3N HCl (5ml) added and let stir at room temperature overnight. The ether layerwas separated and concentrated in vacuo to give 400 mg of the aminehydrochloride product (93%).

Preparative Example 13.12

The title compound was prepared similarly as in Preparative Example13.11, but using the 2-S-methylbenzylamine instead of2-R-methylbenzylamine (69%).

Preparative Example 13.13

Step A

At room temperature, CsF (60 mg) was added to a mixture offurfuraldehyde (1.3 ml) and TMS-CF₃ (2.5 g) and stirred at roomtemperature (24 h) and refluxed for another 12 h. 3N HCl (40 ml) wasadded and after 4 hr, the mixture was extracted with ether, washed withbrine, dried over MgSO₄, and concentrated in vacuo to give the product(2.6 g, 100%).

Step B

To a solution of alcohol from above (2.6 g) in CH₂Cl₂ at roomtemperature was added Dess-Martin reagent (10 g) portionwise and 1 dropof water. After stirring for 3 hr at room temperature, 10% Na₂S₂O₃ (60ml) was added and after stirring overnight, the solid was filtered offand the filtrate was extracted with CH₂Cl₂. The organic layer was washedwith saturated sodium bicarbonate, dried with MgSO₄, filtered andconcentrated in vacuo. Ether/hexane (1:2; 30 ml) was added to theresidue, filtered, and filtrate concentrated in vacuo to give theproduct (2 g, 78%).

Step C

Following the procedures described in Preparative Example 13.11, StepsB, C and D, the amine salt was prepared.

Preparative Examples 13.15-13.17

Following the procedure set forth in Preparative Example 13.13, butusing the prepared or commercially available aldehydes, the opticallypure amine products in the Table below were obtained.

Prep Ex. Aldehyde Amine Product Yield (%) 13.15

20 13.16

31 13.17

66 13.17A

38 13.17B

31

Preparative Example 13.18

The title compound was prepared from trifluorophenylketone according tothe procedures described in Preparative Example 13.11, Steps B, C, and D(68%).

Preparative Example 13.19

Step A

Methyl-3-hydroxy-4-bromo-2-thiophenecarboxylate (10.0 g, 42.2 mmol) wasdissolved in 250 mL of acetone. Potassium carbonate (30.0 g, 217.4 mmol)was added followed by a solution of iodomethane (14.5 mL, 233.0 mmol).The mixture was heated to reflux and continued for 6 h. After cooled toroom temperature, the mixture was filtered, the solid material wasrinsed with acetone (˜200 mL). The filtrate and rinsing wereconcentrated under reduced pressure to a solid, further dried on highvacuum, yielding 13.7 g (100%) ofmethyl-3-methoxy-4-bromo-2-thiophenecarboxylate (MH⁺=251.0).

Step B

Methyl-3-methoxy-4-bromo-2-thiophenecarboxylate (13.7 g), available fromstep A, was dissolved in 75 mL of THF, and added with a 1.0 M sodiumhydroxide aqueous solution (65 mL, 65.0 mmol). The mixture was stirredat room temperature for 24 h. A 1.0 M hydrogen chloride aqueous solutionwas added dropwise to the mixture until pH was approximately 2. Theacidic mixture was extracted with CH₂Cl₂ (100 mL×2, 50 mL). The combinedorganic extracts were washed with brine (40 mL), dried with Na₂SO₄, andconcentrated under reduced pressure to a solid, 10.0 g (100%, over twosteps) of 3-methoxy-4-bromo-2-thiophenecarboxylic acid (MH⁺=237.0).

Step C

To a stirred solution of 3-methoxy-4-bromo-2-thiophenecarboxylic acid(6.5 g, 27.4 mmol) in 140 mL of CH₂Cl₂, obtained from step B, was addedbromo-tripyrrolidinophosphonium hexafluorophosphate (PyBrop, 12.8 g,27.5 mmol), a 2.0 M solution of dimethyl amine in THF (34.5 mL, 69.0mmol), and diisopropylethyl amine (12.0 mL, 68.7 mmol). After 3 d, themixture was diluted with 100 mL of CH₂Cl₂, and washed with a 1.0 Msodium hydroxide aqueous solution (30 mL×3) and brine (30 mL). Theorganic solution was dried with Na₂SO₄, filtered, and concentrated to anoil. This crude oil product was purified by flash column chromatography,eluting with CH₂Cl₂-hexanes (1:1, v/v). Removal of solvents afforded asolid, further dried on high vacuum, yielding 6.76 g (93%) ofN,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide (MH⁺=265.0,M+2=266.1).

Step D

An oven dried three-neck round bottom flask was equipped with arefluxing condenser, charged sequentially with palladium acetate (95 mg,0.42 mmol), (R)-BINAP (353 mg, 0.57 mmol), cesium carbonate (9.2 g,28.33 mmol), and N,N′-dimethyl-3-methoxy-4-bromo-2-thiophenecarboxamide(3.74 g, 14.2 mmol, from step C). The solid mixture was flushed withnitrogen. Toluene (95 mL) was added to the solid mixture followed bybenzophenone imine (3.6 mL, 21.5 mmol). The mixture was heated to refluxand continued for 10 h. A second batch of palladium acetate (95 mg, 0.42mmol) and (R)-BINAP (353 mg, 0.57 mmol) in 5 mL of toluene was added.Refluxing was continued for 14 h. The third batch of palladium acetate(30 mg, 0.13 mmol) and (R)-BINAP (88 mg, 0.14 mmol) was added, andreaction continued at 110° C. for 24 h. The mixture was cooled to roomtemperature, diluted with ether (50 mL), filtered through a layer ofCelite, rinsing with ether. The filtrate and rinsing were concentratedunder reduced pressure to an oil, which was purified twice by flashcolumn chromatography using CH₂Cl₂ and CH₂Cl₂-MeOH (200:1) as eluents.Removal of solvents afforded 4.1 g (79%) of the amido-thiophenediphenylimine product as a solid (MH⁺=365.1).

Step E

To a stirred solution of thiophene imine (5.09 g, 13.97 mmol), obtainedfrom step D, in 140 mL of CH₂Cl₂ at −78° C. was added dropwise a 1.0 Msolution of boron tribromide in CH₂Cl₂. The mixture was stirred for 3 hwhile the temperature of the cooling bath was increased slowly from −78°C. to −15° C. 100 mL of H₂O was added, the mixture was stirred at roomtemperature for 30 min, then the two layers were separated. The organiclayer (as A) was extracted with H₂O (30 mL×2). The aqueous layer andaqueous extracts were combined, washed with CH₂Cl₂ (30 mL), and adjustedto pH ˜8 using a saturated NaHCO₃ aqueous solution. The neutralizedaqueous solution was extracted with CH₂Cl₂ (100 mL×3), the extracts werewashed with brine, dried with Na₂SO₄, and concentrated under reducedpressure to a light yellow solid, 1.49 g ofN,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide (first crop). Theprevious separated organic layer A and organic washing were combined,stirred with 30 mL of a 1.0 M HCl aqueous solution for 1 h. The twolayers were separated, the aqueous layer was washed with CH₂Cl₂ (30 mL)and adjusted to pH ˜8 using a saturated NaHCO₃ aqueous solution, and theseparated organic layer and organic washing were combined as organiclayer B. The neutralized aqueous solution was extracted with CH₂Cl₂ (30mL×4), the extracts were washed with brine, dried by Na₂SO₄, andconcentrated under reduced pressure to give 0.48 g of a solid as thesecond crop of the titled product. Organic layer B from above was washedwith brine, and concentrated to an oil, which was separated bypreparative TLC (CH₂Cl₂-MeOH=50:1) to afford 0.45 g of a solid as thethird crop of the titled product. The overall yield of the product,N,N′-dimethyl-3-hydroxy-4-amino-2-thiophenecarboxamide, is 2.32 g (89%)(MH⁺=187.0).

Preparative Example 13.20

Step A

To the product from Preparative Example 13.19 Step D (1.56 g) in CH₂Cl₂(55 ml) was added potassium carbonate (1.8 g) followed by dropwiseaddition of bromine (0.45 ml). After 5 hr of mixing, water (100 ml) wasadded to the reaction and the layers were separated. The aqueous layerwas extracted with CH₂Cl₂, which was then washed with brine, saturatedsodium bicarbonate, and brine again. The organic layer was dried withNa₂SO₄, and concentrated in vacuo. The residue was purified via flashcolumn chromatography (CH₂Cl₂) to yield 1.6 g of product (83%).

Step B

The product from above was reacted in the procedure set forth inPreparative Example 13.19 Step C to give the amine.

Preparative Example 13.21

Step A

To the product from Preparative Example 13.20, Step A (300 mg) in THF (7ml) at −78° C. was added a solution of n-BuLi (1.6M in hexanes, 0.54ml). After 1 hr, iodomethane (0.42 ml) was added dropwise. After 3 hrsof stirring at −78° C., the reaction was warmed to room temperatureovernight. Saturated ammonium chloride and water were added to thereaction and extracted with CH₂Cl₂. The organic layer was washed withsaturated sodium bicarbonate and brine, dried over Na₂SO₄, andconcentrated in vacuo. The crude product was purified by preparativeplate chromatography (CH₂Cl₂-MeOH=70:1 to 50:1) to afford the product(111 mg, 43%).

Step B

The product from above was reacted in the procedure set forth inPreparative Example 13.19, Step E to give the amine.

Preparative Example 13.22

Step A

To the product from Preparative Example 13.19 (400 mg), Step D inCH₂Cl₂-pyridine (14 ml) was added N-chlorosuccinimide (220 mg). Themixture was stirred for 5 hr and then diluted with CH₂Cl₂ and washedwith water, saturated sodium bicarbonate and brine, and concentrated invacuo. The crude product was purified via preparative platechromatography (CH₂Cl₂-MeOH=50:1) to give 180 mg of product (64%).

Step B

The product from above (274 mg) was reacted in the procedure set forthin Preparative Example 13.19, Step E to give the amine (89 mg, 58%).

Preparative Example 13.23

Step A

To a stirred solution of acid (630 mg) from Preparative Example 13.19,Step B in CH₂Cl₂ (25 ml) was added oxalyl chloride (235 ul) followed bya catalytic amount of DMF (10 ul). The mixture was stirred for 1 hr,then potassium carbonate (1.8 g) was added followed by3-amino-5-methylisoxazole (443 mg). The reaction stirred overnight andwas quenched with water (25 ml). Layers were separated and the organiclayer was washed with brine, dried over Na₂SO₄, and concentrated invacuo. The crude product was purified by preparative platechromatography (CH₂Cl₂) to afford the product (580 mg, 78%, MH+=317,319).

Step B

The acid from the above (750 mg) step was reacted following theprocedure set forth in Preparative Example 13.3, Step B to yield 625 mgof product (80%, MH+=331).

Step C

The product from above was reacted following the procedure set forth inPreparative Example 13.19, Step D to yield 365 mg of product (53%)

Step D

The product from above was reacted following the procedure set forth inPreparative Example 13.19, Step E to give the amine product (MH+=254).

Preparative Example 13.25

Step A

To a solution of 2-methylfuran (1 g) in ether (30 ml) was added n-BuLi(5.32 ml) at −78° C. The reaction was warmed to room temperature andthen refluxed at 38° C. for 1 hr. The reaction was cooled back down to−78° C. where the furyl lithium was quenched with trifluorobutyraldehydeand let stir at room temperature overnight. Saturated ammonium chlorideadded and extracted with ether. Purified via flash column chromatographyto yield pure product (2 g, 80%)

Step B

The azide was prepared using the procedure from Preparative Example75.75, Step B and the alcohol (1 g) from above and carried on crude toStep C below.

Step C

The amine was prepared using the procedure from Preparative Example75.75, Step C to yield 400 mg of an oil (53%).

Preparative Example 13.26

Step A

Perfluoroiodide (3.6 ml) was condensed at −78° C. Ether (125 ml) wasadded followed by the methyllithium.lithiumbromide complex (1.5M inether, 18.4 ml). After 15 min, a solution of 5-methylfuraldehyde (2.5ml) in ether was added dropwise. The reaction was warmed to −45° C. andlet stir for 2 hr. Saturated ammonium chloride (30 ml) and water (30 ml)were added and let stir at room temperature for 1 hr. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂. The organiclayer was washed with brine, dried with Na₂SO₄, filtered andconcentrated in vacuo to give 5.86 g of product (100%).

Step B

The alcohol from above was reacted to form the azide using the procedureset forth in Preparative Example 75.75 Step B.

Step C

The azide from above was reacted to form the racemic amine using theprocedure set forth in Preparative Example 75.75 Step C.

Preparative Example 13.27

Step A

Following the procedure set forth in Preparative Example 13.26, Step A,the alcohol was prepared (100%).

Step B

To a solution of the alcohol (500 mg) from step A above in CH₂Cl₂ (20ml) was added N-methyl-morpholine monohydrate (575 mg) and a catalyticamount of tetrapropyl ammonium perruthenate (76 mg). After 3 hr, themixture was diluted with hexane (10 ml) and filtered through a silicapad, rinsing with hexane: CH₂Cl₂ (200 ml). The filtrate was concentratedin vacuo to give 350 mg of product (70.7%)

Step C

The ketone (1.19 g) from Step B was dissolved in THF (9.5 ml) and cooledto 0° C. A solution of S-methyl oxazoborolidine (1 M in toluene, 1 ml)followed by a solution of borane complexed with dimethylsulfide (9.5 ml,2M in THF) was added to the solution. The mixture was stirred at 0° C.for 30 min and continued at room temperature for 5 hr. The mixture wascooled back down to 0° C. and methanol (15 ml) was added dropwise to themixture. After 30 min, the mixture was concentrated in vacuo to give anoily residue.

The residue was dissolved in CH₂Cl₂ and washed with 1 N HCl, water, andbrine. Dried with Na₂SO₄, filtered and concentrated in vacuo. The crudematerial was purified via flash column chromatography (Hex/CH₂Cl₂, 1:1)to afford 1.14 g of an oil (67%).

Step D

The alcohol (1.14 g) from above was reacted to form the azide using theprocedure set forth in Preparative Example 75.75 Step B.

Step E

The azide (1.11 g) from above was stirred with 10% Pd/C (280 mg) in EtOH(40 ml) under a hydrogen gas atmosphere overnight. The reaction wasfiltered through celite, the filtrate was concentrated in vacuo to give700 mg of product (70%).

Preparative Example 13.28

Step A

To a stirred solution of 1-(2-thienyl)-1-propanone (3 g) in aceticanhydride (6 ml) at 0° C. was added dropwise a solution of fuming nitricacid in acetic acid (2 ml in 10 ml). After 30 min, the reaction waswarmed to room temperature and let stir for 5 hrs where a solidprecipitated out. Ice was added to the reaction and the solid wasfiltered. The solid was purified by flash column chromatography(Hex/CH₂Cl₂, 3:1 and 2:1) to yield 800 mg of desired product (20%).

Step B

The above nitro-thiophene compound (278 mg) was reduced using theprocedure set forth in Preparative Example 2, Step B to give 54 mg ofproduct (23%).

Step C

The above amine (395 mg), TEA (1 ml) and methanesulfonylchloride (0.5ml) were combined in CH₂Cl₂ (35 ml) and stirred at room temperature for1 hr. The reaction was quenched with saturated sodium bicarbonate (15ml). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo to afford product (854 mg, 100%).

Step D

To the above product (854 mg) in THF (25 ml) was added dropwise asolution of tetrabutylammonium fluoride (1M in THF, 2.8 ml). The mixturewas stirred overnight, then diluted with CH₂Cl₂ (30 ml), washed withammonium chloride and brine, dried over over Na₂SO₄, filtered andconcentrated in vacuo to afford product (2.36 g, >100%).

Step E

The ketone (2.36 g) above was reacted via the procedure set forth inPreparative Example 88.2, Step B to yield 547 mg of product (86.6%).

Step F

To the product from step E (310 mg) in dimethoxyethane (12 ml) was addeddropwise a solution of LAH (1M in ether, 3.8 ml). The mixture was heatedto reflux overnight. The reaction was cooled to room temperature, SiO₂was added as well as water (1 ml) dropwise and let stir for 15 min. Themixture was filtered and the filtrate was concentratred in vacuo. Thecrude product was purified by preparative plate chromatography(MeOH/CH₂Cl₂, 15:1) to give the amine product (40 mg, 14%).

Preparative Example 13.29

Step A

To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at−78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture wasstirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, themixture was poured carefully into crushed ice, and extracted withdichloromethane. The extracts were washed with brine, dried overmagnesium sulfate, filtered through a 1-in silica gel pad. The filtratewas concentrated in vacuo to give the desired compound (4.2 g).

Step B

The product from Step A above (4.5 g) was dissolved in dichloromethane(140 mL) and added with triethylamine (8.8 mL) followed by diethyl aminein THF (2M, 21 mL). The resulting mixture was stirred at roomtemperature overnight. The mixture was washed with brine and saturatedbicarbonate (aq) and brine again, dried over sodium sulfate, filteredthrough a 1-in silica gel pad. The filtrate was concentrated in vacuo togive the desired compound (4.4 g).

Step C

The product from Step B above (4.3 g) was dissolved in dichloromethane(125 mL) and cooled in a −78° C. bath. A solution of boron tribromide(1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirredfor 4 h while the temperature was increased slowly from −78° C. to 10°C. H₂O was added, the two layers were separated, and the aqueous layerwas extracted with dichloro-methane. The combined organic layer andextracts were washed with brine, dried over magnesium sulfate, filtered,and concentrated in vacuo to give 3.96 g of the desiredhydroxy-compound.

Step D

The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was addjusted to pH ˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with a 10% Na₂S₂O₃ aqueoussolution and brine, dried over sodium sulfate, and filtered through acelite pad. The filtrate was concentrated in vacuo to afford 4.2 g ofthe desired bromo-compound.

Step E

The product from Step D (4.2 g) was dissolved in 100 mL of acetone andadded with potassium carbonate (10 g) followed by iodomethane (9 mL).The mixture was heated to reflux and continued for 3.5 h. After cooledto room temperature, the mixture was filtered through a Celite pad. Thefiltrate was concentrated in vacuo to a dark brown residue, which waspurified by flash column chromatography eluting withdichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desired product.

Step F

The product from step E (2.7 g) was converted to the desired iminecompound (3 g), following the similar procedure to that of PreparativeExample 13.19 step D.

Step G

The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH ˜6 using 3.0M and 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

Preparative Examples 13.30-13.32-A

Following the procedures set forth in Example 13.29, but usingcommercially available amines, hydroxy-amino-thiophene products in theTable below were obtained.

Yield (%) Prep Ex. Amine Product MH⁺ 13.30 (Bn)₂NH

10% 375.1 13.31 Me(Bn)NH

14% 299.0 13.32 Et(Bn)NH

22% 13.32A (Et)₂NH

25%

Preparative Example 13.33

Step A

2-Chlorosulfonyl-3-methoxy-thiophene (4.0 g, 18.8 mmol), the productfrom Step A of Preparative Example 13.29 was converted to3-methoxy-2-ethylbenzylsulfonyl-thiophene (5.5 g, 94%, MH⁺=312.1) byusing ethylbenzyl-amine, following the procedure set forth inPreparative Example 13.29, Step B.

Step B

The product from Step A above (5.5 g, 17.70 mmol) was demethylatedfollowing the procedure set forth in Preparative Example 13.29, Step C.The alcohol product was obtained in 4.55 g (87%, MH⁺=298.0).

Step C

The product from Step B above (4.55 g, 15.30 mmol) was brominated usingthe procedure set forth in Preparative Example 13.29, Step D. Thecorresponding bromide was obtained in 4.85 g (84%).

Step D

The bromo-alcohol from Step C above (4.84 g, 12.86 mmol) was methylatedusing the procedure set forth in Preparative Example 13.29, Step E. Theproduct was obtained in 4.82 g (96%).

Step E

The product from Step D above (4.82 g, 12.36 mmol) was stirred withconcentrated sulfuric acid (5 mL) at room temperature ro 3 h. Ice water(30 mL) was added to the mixture followed by CH₂Cl₂ (50 mL). The aqueousmixture was adjusted to pH ˜6 using a 1.0 M NaOH aqueous solution. Thelayers were separated. The aqueous layer was extracted with CH₂Cl₂ (50mL×3). The combined organic layers were washed with brine, dried overNa₂SO₄, and concentrated to a dark brown oil, which was purified byflash column chromatography, eluting with CH₂Cl₂-hexanes (1:1, v/v).Removal of solvents afforded 3.03 g (82%) of the debenzylated product(M⁺=300.0, M+2=302.0).

Step F

The product from Step E (1.34 g, 4.45 mmol) was methylated using theprocedure set forth in Preparative Example 13.29, Step E. The desiredproduct was obtained in 1.36 g (97%, M⁺=314.1, M+2=316.0).

Step G

The product from Step F (1.36 g, 4.33 mmol) was converted to imineproduct (1.06 g, 55%, MH⁺=415.1) using the procedure set forth inPreparative Example 13.29, Step F.

Step H

The imine product from Step G (1.06 g, 2.56 mmol) was converted to thedesired hydroxy-amino thiophene compound (0.26 g, 43%) using theprocedure set forth in Preparative Example 13.29, Step G.

Preparative Example 13.34

Step A

2-Chlorosulfonyl-3-methoxy-thiophene (3.8 g, 17.87 mmol), the productfrom step A of Preparative Example 13. 29, was dissolved in 100 mL ofCH₂Cl₂ and 20 mL of pyridine. 3-Amino-5-methyl-isoxazole (3.5 g, 35.68mmol) was added. The mixture was stirred for 20 h at room temperature,diluted with 100 mL of CH₂Cl₂, and washed with a 0.5 N HCl aqueoussolution (50 mL×2), H₂O (50 mL), and brine (50 mL). The organic solutionwas dried with Na₂SO₄, and conentrated in vacuo to a brown oil. This oilwas dissolved in 100 mL of CH₂Cl₂, washed again with a 0.5 M HCl aqueoussolution (30 mL×3) and brine. After dried over Na₂SO₄, the organicsolution was concentrated in vacuo to a yellow solid, 4.48 g (91%,MH⁺=275.0) of the desired product.

Step B

The product from Step A above (4.48 g, 16.33 mmol) was dissolved inacetone (100 mL), added with potassium carbonate (5.63 g, 40.80 mmol)and iodomethane (10.1 mL, 163.84 mmol). The mixture was stirred at roomtemperature for 1.5 h, diluted with 100 mL of hexanes and 50 mL ofCH2Cl2, and filtered through a 1-in silica gel pad, rinsing with CH2Cl2.The filtrate was concentrated under reduced pressure to give 4.23 g(90%, MH⁺=289.0) of the desired product as a light yellow solid.

Step C

To a stirred suspension of sodium hydride (130 mg, 95%, 5.4 mmol) in 8mL of N,N′-dimethylforamide at room temperature was added ethanethiol(0.45 mL, 6.0 mmol) dropwise. After 5 min, the mixture became a clearsolution, and was added to a stirred solution of the product obtainedfrom Step B above (0.45 g, 1.56 mmol) in 2 mL of N,N′-dimethylforamidein a round bottom flask. The flask was sealed with a ground glassstopper, and the mixture was heated at 90-95° C. for 4 h. After cooledto room temperature, the mixture was poured into 20 mL of a 1.0 M NaOHaqueous solution, further rinsed with 20 mL of H₂O. The aqueous mixturewas washed with diethyl ether (30 mL×2), adjusted to PH ˜5 using a 0.5 MHCl aqueous solution, and extracted with CH₂Cl₂ (50 mL×4). The combinedextracts were washed with brine, dried (Na₂SO₄), and concentrated to adark yellow solution. This was dissolved in 50 mL of ethyl acetate,washed with H₂O (30 mL×2) and brine (30 mL), dried over Na₂SO₄.Evaporation of solvent gave 0.422 g of the alcohol product (99%,MH⁺=275.0).

Step D

The alcohol obtained from Step C above (0.467 g, 1.70 mmol) wasbrominated using the procedure set forth in Preparative Example 13.29,Step D, to afford the corresponding bromide in 0.607 g (100%).

Step E

The bromide obtained from Step D above (0.607 g, 1.72 mmol) wasmethylated using the procedure set forth in Preparative Example 13.29,Step E, to give the desired product in 0.408 g (65%, M⁺=367, M+2=369.1).

Step F

The product (0.405 g,1.103 mmol) from Step E above was converted to theimine compound (0.29 g, 56%) using the procedure set forth inPreparative Example 13.29, Step F.

Step G

The imine product obtained from Step F above (0.29 g, 0.61 mmol) wasdemethylated using the procedure set forth in Step C above to give thecorresponding alcohol as a dark yellow oil, which was dissolved in 5 mLmethanol and added with sodium acetate (0.12 g, 1.46 mmol) andhydroxyamine hydrochloride (0.075 g, 1.08 mmol). The resulting mixturewas stirred at room temperature for 3 h, and poured into 10 mL of 1.0 MNaOH aqueous solution. 30 mL of H₂O was used as rinsing and combined tothe aqueous layer. The aqueous mixture was washed with diethyl ether (40mL×3), adjusted to pH ˜6 using a 1.0 M HCl aqueous solution, andextracted with ethyl acetate (40 mL×3). The organic extracts were washedwith H₂O (20 mL×2), brine (20 mL), dried over Na₂SO₄, and concentratedin vacuo to give 0.112 g of the desired hydroxy-amino thiophenesulfonamide (64%, MH⁺=290).

Preparative Example 13.35

Step A

To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38mL) at −78° C. and stirred at room temperature for half an hour. Thereaction mixture again cooled to −78° C. and quenched with cyclopropylamide 1 and stirred for two hours at −78° C. and slowly warmed to roomtemperature. The reaction mixture stirred for three hours at roomtemperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

Step B

To a solution of ketone (1.0 g) in THF (5.0 mL) at 0° C. was addedR-methyl oxazoborolidine (1.2MI, 1 M in toluene) dropwise followed byaddition of a solution of borane complexed with dimethyl sulfide (1.85mL, 2M in THF). The reaction mixture was stirred for 30minutes at 0° C.and than at room temperature for one hour. The reaction mixture wascooled to 0° C. and MeOH was added carefully. The mixture was stirredfor 20 minutes and was concentrated under reduced pressure. The residuewas extracted with ether, washed with water, 1M HCl (10 mL), saturatedsodium bicarbonate (10.0 mL) water and brine. The organic layer wasdried over anhydrous sodium sulfate, filtered and removal of solventafforded the crude alcohol which was purified by silica gelchromatography to afford the pure alcohol 0.91 g (91 %) as yellow oil.

Preparative Example 13.36

Step A

An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) wasmixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours. Aftercooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

Step B

The step B alcohol was obtained following a similar procedure set forthin the preparative example 13.35 Step B.

Preparative Example 13.37

Step A

To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silicagelchromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 13.38-13.45

Following a similar procedure set forth in Preparative Examples 13.25and 13.35, and using the indicated Furan and Electrophile, the followingAlcohols in the Table below were prepared.

Prep. ex Furan Electrophile Alcohol Yield 13.38

86% 13.39

69% 13.40

84% 13.41

82% 13.42

60% 13.43

65% 13.44

82% 13.45

89%

Preparative Examples 13.50-13.61

Following a similar procedure set forth in Preparative Examples 13.25,and using the indicated Alcohol, the following Amines in the Table belowwere prepared.

PREP. EX. ALCOHOL AMINE % YIELD 13.50 13.45

28% 13.51 13.38

58% 13.52 13.36

69% 13.53 13.35

81% 13.54 13.37

82% 13.55 13.39

45% 13.56 13.41

57% 13.57 13.40

58% 13.58 13.44

54% 13.59 13.42

53% 13.60 13.43

50% 13.61 13.37

82%

Preparative Example 13.70

Step A

The imine was prepared following the procedure set forth in thepreparative example 13.19 from the known bromoester (1.0 g) as a yellowsolid, Step A to yield 1.1 g (79%).

Step B

The Step A product (0.6 g) was reacted following the procedure set forthin the preparative example 13.19 to give the amine product 0.19 g (64%).

Step C

The Step B product (1.0 g) was reacted following the procedure set forthin the preparative example 13.19 to give the acid as yellow solid 0.9 g(94%)

Step D

The Step C product (0.35 g) was reacted following the procedure setforth in the preparative example 13.19 to give the amino acid as yellowsolid 0.167 g (93%).

Preparative Example 13.71

Following a similar procedure set forth in Preparative Example 13.33Step E, but using the product from Preparative Example 13.32, the titlecompound was obtained (121 mg, 69% yield, MH+=223.0).

Preparative Example 14

Step A

3-Nitro-1,2-phenylenediamine(10 g), sodium nitrite (5.4 g) and aceticacid (20 mL) were heated at 60° C. overnight, then concentrated invacuo, diluted with water and extracted with EtOAc. The productprecipitated from the organic phase (5.7 g) as a solid and used directlyin step B.

Step B

The product from Step A above (2.8 g) was stirred with 10% Pd/C (0.3 g)in MeOH (75 mL) under a hydrogen gas atmosphere overnight. The reactionmixture was filtered through celite and the filtrate concentrated invacuo, to give the product (2.2 g, MH+=135).

Preparative Example 15

Step A

N-methyl-4-bromopyrazole-3-carboxylic acid was prepared according toknown methods, see: Yu. A. M.; Andreeva, M. A.; Perevalov, V. P.;Stepanov, V. I.; Dubrovskaya, V. A.; and Seraya, V. I. in Zh. Obs. Khim,(Journal of General Chemistry of the USSR) 1982, 52, 2592 (and thereferences cited therein) the disclosure of whichis incorporatedhereinby reference thereto.

Step B

To a solution of N-methyl-4-bromopyrazole-3-carboxylic acid (2.0 g),available from step A, in 65 mL of anhydrous DMF was addedbromotripyrrolidinophosphonium hexafluorophosphate (PyBrop, 4.60 g),dimethyl amine (10 mL, 2.0 M in THF) and diisopropylethyl amine (5.2 mL)at 25° C. The mixture was stirred for 26 h, and concentrated underreduced pressure to an oily residue. This residue was treated with a 1.0M NaOH aqueous solution, and extracted with ethyl acetate (50 mL×4). Theorganic extracts were combined, washed with brine, and dried withanhydrous Na₂SO₄. Removal of solvents yielded an oil, which was purifiedby preparative thin layer chromatography, eluting with CH₂Cl₂-MeOH(20:1), to give 1.09 g of the amide product (48%, MH⁺=232.0).

Step C

To a solution of the amide (0.67 g), obtained from step B, in 8 mL ofconcentrated sulfuric acid at 0° C. was added potassium nitrate (1.16 g)in small portions. The cooling bath was removed and the mixture washeated at 110° C. for 6 h. After cooling to 25° C., the mixture waspoured into 80 mL of H₂O, and an additional 20 mL of H₂O was used as arinse. The aqueous mixture was extracted with CH₂Cl₂ (100 mL×4). Thecombined extracts were washed with brine (50 mL), sat. NaHCO₃ aqueoussolution (50 mL), brine (50 mL), and dried with Na₂SO₄. Evaporation ofsolvent gave an oil, which solidified on standing. The crude product waspurified by flash column chromatography, eluting with CH₂Cl₂-MeOH (1:0,50:1 and 40:1). Removal of solvents afforded 0.521 g (65%) of theproduct as a solid (MH⁺=277.1)

Step D

The product (61 mg) obtained from step C was dissolved in 3 mL of THF.To this solution at −78° C. was added dropwise along the inside wall ofthe flask a 1.6 M solution of n-butyl lithium in hexane. After 45 min, asolution of methyl borate (0.1 mL) in THF (1.0 mL) was added. After 1.5h, a solution of acetic acid in THF (0.25 mL, 1:10 v/v) was added to thecold mixture. Stirring was continued for 10 min, and a 30 wt % aqueoushydrogen peroxide solution (0.1 mL) was added. An additional portion ofhydrogen peroxide aqueous solution (0.05 mL) was added 20 min later. Thecooling bath was removed, and the mixture was stirred at 25° C. for 36h. The mixture was poured into 30 mL of H₂O, and the aqueous mixture wasextracted with ethyl acetate (30 mL×4). The extracts were combined,washed with brine (10 mL), 5% NaHCO₃ aqueous solution (10 mL) and brine(10 mL). The organic layer was dried with Na₂SO₄ and concentrated underreduced pressure to a residue, which was then purified by preparativethin layer chromatography eluting with CH₂Cl₂-MeOH (20:1) to give thehydroxylated product (5 mg, 10%, MH⁺=215.3).

Step E

By treating the hydroxylated product of Step E with H₂ under theconditions of 10% palladium on carbon in ethanol, one would obtain thedesired hydroxyl-amino compound.

Preparative Example 16

Step A

Following a similar procedure used in Preparative Example 13, Step Cexcept using the known compound, 4-methyl-pyrimidin-5-ol, the productcan be prepared.

Step B

Following a similar oxidation procedure used in Preparative Example 15,Step A except using the compound from Step A above, the product can beprepared.

Step C

Following a similar procedure used in Preparative Example 11, Step Aexcept using the compound from Step B above, the product can beprepared.

Step D

Following a similar procedure used in Preparative Example 12, Step Fexcept using the compound from Step C above, the product can beprepared.

Preparative Example 17

Step A

Following a similar procedure used in Preparative Example 11, Step Aexcept using the known 4-hydroxynicotinic acid, the product can beprepared.

Step B

Following a similar procedure used in Preparative Example 13, Step Cexcept using the compound from Step A above, the product can beprepared.

Step C

Following a similar procedure used in Preparative Example 12, Step Fexcept using the compound from Step C above, the product can beprepared.

Preparative Example 18

Step A

Following a similar procedure used in Preparative Example 13, Step Cexcept using the compound from Step A above, the product can beprepared.

Step B

Stirring the compound from Step A above, a suitable Pt or Pd catalystand EtOH under hydrogen atmosphere (1-4 atm) the product can beprepared.

Preparative Example 19

The amine was prepared following WO 01/68570, the disclosure of whichisincorporated herein by reference thereto.

Preparative Example 19.1

The amine was prepared following WO 01/68570, the disclosure of which isincorporated herein by reference thereto.

Prepartive Example 20

The title compound was prepared according to the procedure set forth inPreparative Example 1, but instead using 4-nitrosalycilic acid (57%,MH+=181).

Preparative Example 22

The title compound is prepared according to the procedure outlined in J.Org. Chem, V 48, No: 6, 1983, P 763-767.

Preparative Example 22.1

Following a similar procedure outlined in J. Org. Chem, V 48, No: 6,1983, P 763-767, but using the sulfonamide prepared in IzvestiyaAkademii Nauk SSSR, Seriya Khimicheskaya (1978), (9), 2084-90, the titlecompound could be prepared.

Preparative Example 22.2

Following a similar procedure outlined in J. Org. Chem, V 48, No: 6,1983, P is 763-767, but using the sulfonamide prepared in Journal ofOrganic Chemistry (1959), 24, 1983-6, the title compound could beprepared.

Preparative Example 22.3

Step A

If one were to treat the commercially availablechloroacetylsulfonylchloride with dimethyl amine (1 eq) in THF accordingto standard procedures, the sulfonyl chloride intermediate could beobtained.

Step B

Following a similar procedure outlined in J. Org. Chem, V 48, No:6,1983, P 763-767, but using the product from Step A above, the titlecompound could be prepared.

Preparative Example 22.4

Following a similar procedure outlined in J. Org. Chem, V 48, No: 6,1983, P 763-767, but using the sulfonamide prepared in BioorganicChemistry (1996), 24(3), 242-250, the title compound could be prepared.

Preparative Example 23.10A

Following a similar procedure as that used in the Preparative Example1302 Steps A-C, except using pyrrolidine in Step A instead of diethylamine and 50 psi hydrogen pressure in the hydrogenation Step C, thetitle compound was obtained (80%, 1.0 g, MH⁺=243.1)

Preparative Example 23.10B

Following the same procedure set forth in the Preparative Example23.10A, except by using 30 psi hydrogen pressure in the hydrogenationStep C, the title compound was obtained (83%, 1.2 g, MH⁺=277.1).

Preparative Example 24

Step A

To a solution of N-protected amino acid (1.5 g, 6.9 mmol) in CH₂Cl₂ (25mL) at room temperature was added DIPEA (3.6 mL, 20.7 mmol), and PyBrop(3.4 g, 6.9 mmol) followed by MeNH₂ (6.9 mL, 13.8 mmol, 2.0 M inCH₂Cl₂). The resulting solution was stirred for 18 h at room temperature(until TLC analysis deemed the reaction to be complete). The resultingmixture was washed sequentially with 10% citric acid (3×20 mL), sat. aq.NaHCO₃ (3×20 mL), and brine (3×20 mL). The organic layer was dried(Na₂SO₄), filtered, and concentrated under reduced pressure. The crudeproduct was purified by flash chromatography eluting with CH₂Cl₂/MeOH(40:1) to afford 1.0 g (63% yield) of a solid.

Step B

To a round bottom charged with the N-protected amide (1.0 g, 4.35 mmol)(from Step A) was added 4N HCl/dioxane (10 mL) and the mixture wasstirred at room temperature for 2 h. The mixture was diluted with Et₂O(20 mL) and concentrated under reduced pressure. The crude product wastreated with Et₂O (2×20 mL) and concentrated under reduced pressure toafford 0.72 g (˜100% yield) of crude product as the HCl salt. Thismaterial was taken on without further purification or characterization.

Preparative Examples 25-33.1

Following the procedure set forth in Preparative Example 24 but usingthe commercially available N-protected amino acids and amines in theTable below, the amine hydrochloride products were obtained.

Prep Yield Ex. Amino acid Amine Product (%) 25

NH₃

70 26

71 27

66 28

65 29

90 30

68 31

68 32

97 33

97 33.1

20

Preparative Example 33.2

Step A

BOC-valine (45 mg) and PS-carbodiimide (200 mg) were suspended in CH₂Cl₂(4 ml). After addition of the CH₂Cl₂-amine solution (0.138N, 1 ml), themixture was shaken overnight. The solution was filtered and the resinwas washed with more CH₂Cl₂, and the filtrate was concentrated in vacuoto yield the product, which was carried on directly in Step B.

Step B

The crude material from Step A was dissolved in 4N HCl/dioxane (2.5 ml)and stirred for 2 h. The reaction was concentrated in vacuo to yield thedesired amine hydrochloride, which was used directly in the next step.

Preparative Examples 33.3-33.47

Following the procedure set forth in Example 33.2 but using thecommercially available N-protected amino acids in the Table below, theamine hydrochloride products were obtained.

Prep Ex. Amino acid Amine Product 33.3

33.4

33.5

33.6

33.7

33.8

33.9

33.10

33.11

33.12

33.13

33.14

33.15

33.16

33.17

33.18

19

33.20

33.21

33.22

33.23

33.24

33.25

33.26

33.27

33.28

33.29

33.30

33.31

33.32

33.33

33.34

33.35

33.36

33.37

33.38

33.39

33.40

33.41

33.42

33.43

33.43

33.45

33.46

33.47

Preparative Example 34

To a solution of 3-chlorobenzaldehyde (2.0 g, 14.2 mmol) in THF (5 mL)at 0° C. was added LiN(TMS)₂ (17.0 ml, 1.0 M in THF) dropwise and theresulting solution was stirred for 20 min. EtMgBr (6.0 mL, 3.0 M inEt₂O) was added dropwise and the mixture was refluxed for 24 h. Themixture was cooled to room temperature, poured into saturated aqueousNH₄Cl (50 mL), and then extracted with CH₂Cl₂ (3×50 volumes). Theorganic layers were combined, concentrated under reduced pressure. Thecrude residue was stirred with 3 M HCl (25 mL) for 30 min and theaqueous layer was extracted with CH₂Cl₂ (3×15 mL) and the organic layerswere discarded. The aqueous layer was cooled to 0° C. and treated withsolid NaOH pellets until pH=10 was attained. The aqueous layer wasextracted with CH₂Cl₂ (3×15 mL) and the organic layers were combined.The organic layer was washed with brine (1×25 mL), dried (Na₂SO₄), andconcentrated under reduced pressure to afford 1.6 g (66% yield) of thecrude amine as an oil (MH⁺170). This material was determined to be >90%pure and was used without further purification.

Preparative Example 34.1

The aldehyde (3.5 g) and conc. HCl (20 ml) were combined and stirredovernight at 40° C. The reaction mixture was poured into cold water andextracted with ether, washed with satd. NaHCO₃ and brine, dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give 1.76 g ofproduct (55%)

Preparative Example 34.2

Chlorine was bubbled into 100 ml of CH₂Cl₂ at 10° C. The aldehyde (3.73ml) was charged with 50 ml of CHCl₃ and then cooled to 0° C. AlCl₃ wasadded portionwise, followed by the chlorine solution and let stir atroom temperature overnight. The reaction was poured into 150 ml of iceand 50 ml of 3N HCl and stirred for 30 min. Organic layer was washedwith brine, dried with Na₂SO₄, and concentrated in vacuo. The crudeproduct was purified via flash column chromatography (Hex/EtOAc 40/1) toyield 1.5 g of pure product.

Preparative Example 34.3

Step A

The ketone (3.25 g) was reacted following the procedure set forth inPreparative Example 88.2, Step B to give the oxime (3.5 g, 99%).

Step B

The product from step A (1.2 g) was stirred with AcOH (3 ml) and Pd/C(10%, 300 mg) in EtOH (40 ml) under a hydrogen atmosphere overnight. Thereaction mixture was filtered through celite and the filtrate wasconcentrated in vacuo. The crude material dissolved in ether and washedwith 2N NaOH, organic washed with brine, dried with Na₂SO₄, andconcentrated in vacuo to give product (960 mg, 86%).

Preparative Example 34.4

Step A

To a suspension of NaH (1.45 g) in DMF (25 ml) under a nitrogenatmosphere was added p-bromophenol (5 g) at 0° C. After stirring for 20min, BrCH₂CH(OEt)₂ (5.3 ml) was added and the reaction was heated toreflux overnight. The solution was cooled and poured into ice water (80ml) and extracted with ether. The ether layer was washed with 1N NaOHand brine, dried with MgSO₄, filtered and concentrated in vacuo to give8.4 g of crude product (100%)

Step B

To a solution of the product from Step A (8.4 g) in benzene (50 ml) wasadded polyphosphoric acid (10 g). The mixture was heated at reflux for 4hrs. The reaction was cooled to 0° C. and poured into ice water (80 ml)and extracted with ether. The ether layer was washed with saturatedsodium bicarbonate and brine, dried with MgSO₄, filtered andconcentrated in vacuo to give 4.9 g of crude product (85%)

Step C

To a solution of the product from Step B (2 g) in ether (20 ml) at −78°C. was added t-BuLi dropwise. After stirring for 20 min, DMF (950 mg)was added dropwise and the mixture was stirred at −25° C. for 3 hrs andthen warmed to room temperature overnight. Saturated ammonium chloridewas added and the solution was extracted with ether. The ether layer waswashed with brine, dried with MgSO₄, filtered and concentrated in vacuoto give 980 mg of crude product (67%).

Step D

To a solution of aldehyde (400 g) in ether (10 ml) was added LiN(TMS)₂(1M in THF, 3.3 ml) at 0° C. dropwise. The solution was stirred at 0° C.for 30 min and EtMgBr (3M in THF, 1.83 ml) was added dropwise. Thereaction was refluxed overnight, cooled to 0° C., quenched withsaturated ammonium chloride and extracted with ether. The ether wasstirred with 3N HCl (20 ml), then the aqueous layer was basified withNaOH pellets and extracted with ether. The ether layer was washed withbrine, dried with MgSO₄, filtered and concentrated in vacuo to give 220mg of product (46%).

Preparative Example 34.5

Following the procedures set forth in Preparative Example 34.4 Steps Athrough D, but using m-bromophenol (8 g), both amines were formed andseparated by preparative plate chromatography (63-65%, MH+=175).

Preparative Example 34.6

To a solution of 3-methyl-thiophene (5 g) in ether (50 ml) was addeddropwise a solution of n-BuLi (1.6M in hexane, 32 ml). The mixture wasstirred for 1.5 hr at room temperature. DMF (5.1 ml) was then added andlet stir overnight. The mixture was poured into saturated ammoniumchloride and extracted with ether. The ether layer was washed withbrine, dried with Na₂SO₄, and concentrated in vacuo. The crude productwas purified via flash column chromatography (EtOAc/Hex 20:1) to afford5.27 g of an oil (84%).

Preparative Example 34.7

Step A

To a solution of 4-bromo-2-furaldehyde (4 g) in MeOH (75 ml) was addedtrimethyl-orthoformate (3.8 ml). A catalytic amount of p-toluenesulfonic acid (195 mg) and the mixture was heated to reflux for 3.5 hr.The reaction was cooled down and potassium carbonate was added. Themixture was filtered through a silica gel pad. The filtrate wasconcentrated in vacuo, dissolved in CH₂Cl₂ and filtered. The filtratewas again concentrated in vacuo to give 4.03 g of product (80%).

Step B

To a solution of the product from Step A (2.02 g) in THF (80 ml) at −78°C. was added dropwise a solution of n-BuLi (2.5M in hexanes, 4.4 ml) andstirred for 1.5 hr. A solution of iodomethane (1.7 ml) was added and letstir for 2.5 hrs at −60° C. The cooling bath was removed and saturatedammonium chloride was added and let stir for 10 min. The layers wereseparated and the organic layer was washed with brine, dried withNa₂SO₄, and concentrated in vacuo to afford 1.34 g of crude product.

Step C

The product from Step B (1.43 g) was dissolved in acetone (50 ml) andtreated with a catalytic amount of p-toluene sulfonic acid (80 mg). Themixture was heated to reflux for 2 hr. The reaction was cooled down andsolid potassium carbonate was added. The mixture was filtered through asilica gel pad and the filtrate was concentrated in vacuo to give 1.246g of crude product.

Preparative Example 34.8

Step A

To a stirred solution of potassium t-butoxide (2.5 g) in HMPA (20 ml)was added 2-nitropropane (2 ml) dropwise. After 5 min, a solution ofmethyl-5-nitro-2-furoate (3.2 g) in HMPA (8 ml) was added to the mixtureand stirred for 16 hr. Water was added and the aqueous mixture wasextracted with EtOAc. The EtOAc layer was washed with water, dried withMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6 gof product (90%).

Step B

To a solution of the product from Step A (3.6 g) in toluene (16 ml) wasadded tributyltin hydride (5.4 ml) followed by AIBN (555 mg). Themixture was heated to 85° C. for 3.5 hr. After cooling, the mixture wasseparated by flash column chromatography (Hex/EtOAc, 7:1) to afford 2.06g of product (73%).

Step C

To a solution of product from Step B (2.05 g) in THF (60 ml) at 0° C.was added a solution of LAH (1M in ether, 12.8 ml). The reaction wasstirred at room temperature for 30 min. Water and 1M NaOH was addeduntil a precipitate formed, diluted with EtOAc, stirred for 30 min andthen filtered through a celite pad. The organic filtrate wasconcentrated in vacuo to give 1.56 g of product (93%).

Step D

To a solution of product from Step C (2.15 g) in CH₂Cl₂ (100 ml) wasadded Dess-Martin oxidant (7.26 g) in CH₂Cl₂ (45 ml) and stirred for 30min. The mixture was diluted with ether (200 ml). The organic layer waswashed with 1N NaOH, water and brine, dried with MgSO₄, filtered andconcentrated in vacuo to give oil and solid. The material was extractedwith ether and filtered. Some solid crystallized out from the filtrate,filtered again, and the filtrate was concentrated in vacuo to give 2.19g of product.

Preparative Example 34.9

Step A

To a solution of carboxylic acid (5 g) in CH₂Cl₂ (400 ml) at 0° C. wasadded N(OCH₃)CH₃.HCl (11.5 g), DEC (15.1 g), HOBt (5.3 g) and NMM (43ml) and stirred for 14 hr. The mixture was diluted with CH₂Cl₂ (100 ml)and the organic layer was washed with 10% HCl, saturated sodiumbicarbonate and brine, dried with Na₂SO₄, and concentrated in vacuo toafford 5.74 g of crude product (85%).

Step B

To a solution of iodoethane (0.56 ml) in ether (5 ml) at −78° C. wasadded a solution of t-BuLi (1.7M in pentane, 8.3 ml) dropwise. Themixture was warmed to room temperature for 1 hr and transferred to a 100ml round bottom charged with the product from Step A (1 g) in THF (12ml) at −78° C. The mixture was stirred at −78° C. for 1 hr and at 0° C.for an additional 2 hr. 1M HCl was added dropwise followed by CH₂Cl₂.The layers were separated and the organic layer was washed with brine,dried with Na₂SO₄, and concentrated in vacuo to afford 620 mg of product(76%).

Step C

To a solution of the product from Step B (620 mg) in THF/MeOH (10:1) at0° C. was added NaBH₄ (250 mg) in one portion. The mixture was stirredovernight at 0° C., concentrated in vacuo and the crude material wasdissolved in CH₂Cl₂ and washed with 1N NaOH and brine, dried withNa₂SO₄, and concentrated in vacuo to afford 510 mg of product.

Step D

The above material was reacted in the procedures set forth inPreparative Example 75.75 Steps B and C to yield 170 mg of amine product(28%).

Preparative Example 34.10

The above amine was made analogous to the procedures set forth in PatentWO96/22997 p.56 (the disclosure of which is incorporated herein byreference thereto), but using ethylglycine instead of benzylglycine inthe DCC coupling.

Preparative Example 34.11

Step A

To the nitro compound (3.14 g) and cyclohexylmethanol (1.14 g) in THF(50 ml) was added PPH₃ (4.72 g) and cooled to 0° C.Diisopropylazadicarboxylate (3.15 ml) was added dropwise and let stirovernight. The reaction was concentrated in vacuo and purified via flashcolumn chromatography (Hex/EtOAc, 30:1) to give product (3.3 g), whichwas carried on directly to the next step.

Step B

To the product from step A (3.3 g) in EtOH (50 ml) was added 10% Pd/C(1.7 g) under a hydrogen atmosphere at 55 psi and let stir overnight.The reaction was filtered through celite and concentrated in vacuo togive 3.2 g of product.

Preparative Example 34.12

Step A

A solution of acid (2 g) in ether (20 ml) was added dropwise to asuspension of LiAlH₄ (350 mg) in ether (15 ml) at 0° C. The solution wasrefluxed for 3 hr and stirred at room temperature overnight. 5% KOH wasadded and reaction was filtered, extracted with ether, dried with MgSO₄,filtered and concentrated in vacuo to give the product (1.46 g, 79%,MH+=166).

Step B

To a solution of alcohol from above (1.46 g) in CH₂Cl₂ at roomtemperature was added Dess-Martin reagent (5.6 g) portionwise and onedrop of water and let stir over the weekend at room temperature. 10%Na₂S₂O₃ was added and stirred for 20 min, extracted with CH₂Cl₂, washedwith saturated sodium bicarbonate, dried with Na₂SO₄, and concentratedin vacuo to afford 1.1 g of product (76%).

Preparative Example 34.13

The above compound was prepared according to the procedure set forth inEP 0 555 153 A1 (the disclosure of which is incorporated herein byreference thereto).

Preparative Example 34.14

The aldehyde (500 mg) from above was reacted following the procedure setforth in the Preparative Example 13.4, Step A to yield 372 mg of product(76%).

Preparative Example 34.15-34.16

Following the procedures set forth in Preparative Example 34.8 but usingthe nitroalkanes indicated in the table below, the aldehydes wereprepared.

PREP. YIELD Ex. NITROALKANE ALDEHYDE (%) 34.15

17 34.16

21

Preparative Example 34.17

Step A

To a stirred suspension of 5-bromo-2-furoic acid (15.0 g, 78.54 mmol) in225 mL of CH₂Cl₂ at room temperature was added oxalyl chloride followedby a catalytic amount of N,N′-dimethylforamide. After 1 h, ethanol (20mL) was added followed by triethylamine (22 mL). Reaction was continuedfor 15 h. The mixture was concentrated under reduced pressure to aresidue, which was extracted with excess volume of hexanes, andhexanes-CH₂Cl₂ (3:1, v/v). The extracts were filtered, the filtrated wasconcentrated to a yellow oil, dried on high vacuum, yielding 17.2 g(93%) of the desired ester.

Step B

The ester product obtained from Step A above (17.2 g, 73.18 mmol) wasconverted to 2-ethyl-4-tertbutyl-5-bromo-furoate (7.9 g, 37%) using theliterature procedure: J. Am. Chem.Soc., 1939, 61, 473-478 (thedisclosure of which is incorporated herein by reference thereto).

Step C

The ester product obtained from Step B above (7.9 g, 27.13 mol) wasreduced to the alcohol (6.32 g) using the procedure set forth inPreparative Example 34.8, Step C.

Step D

The product obtained from Step C above (6.32 g) was dissolved in 140 mLof THF and cooled in a −78° C. bath. A 2.5 M solution of n-butyllithiumin hexanes (22 mL, 55.0 mmol) was added dropwise along the side wall ofthe flask. After 15 min, H₂O (˜70 mL) was added. Cooling bath wasremoved, the mixture was stirred for an additional 1 h. Brine (50 mL)and CH₂Cl₂ (300 mL) were added, the two layers were separated, theaqueous layer was extracted with CH₂Cl₂ (100 mL), and the combinedorganic layers were dried by Na₂SO₄. Evaporation of solvents afforded5.33 g (crude) of the debrominated product as a reddish brown oil.

Step E

The alcohol product obtained from Step D above (5.33 g) was oxidized tothe corresponding aldehyde (3.06 g, 74% over three steps) using theprocedure set forth in Preparative Example 34.8, Step D.

Preparative Example 34.18

Step A

To a stirred solution of cyclopropyl bromide (4.0 mL, 50 mmol) in 120 mLof ether at −78° C. was added dropwise a 1.7M solution of t-butyllithiumin pentane (44.5 mL, 75.7 mmol). After 10 min, cooling bath was removed,stirring was continued for 1.5 h. The mixture was cooled again in a −78°C. bath, and 3-furaldehyde (3.5 mL, 41.9 mmol) was added. Reaction wascontinued for 1 h, and quenched with a saturated NH4Cl aqueous solution.The aqueous mixture was extracted with CH₂Cl₂ (100 mL×3). The organicextracts were washed with brine, dried by Na₂SO₄, filtered, andconcentrated in vacuo to give 5.3 g (91%) of the alcohol product as ayellow oil.

Step B

Chloro trimethylsilane (27.2 mL, 214.2 mmol) was added dropwise to avigorously stirred suspension of sodium iodide (32 g, 213.5 mmol) in 100mL of acetonitrile. After 5 min, a solution of the alcohol obtained fromStep A above (4.93 g, 35.68 mmol) in 100 mL of acetonitrile was addeddropwise. Stirring was continued for 5 min. H₂O (100 mL) was added, thelayers were separated, and the aqueous layer was extracted with ether(100 mL×2). The organic layers were combined, washed with a 10% Na₂S₂O₃aqueous solution and brine, and dried over Na₂SO₄. Evaporation ofsolvents gave a dark brown oil, which was filtered through a 5-in silicagel column, eluting with CH₂Cl₂-hexanes (1:3.5, v/v). Removal ofsolvents afforded 4.22 g (47%) of the iodo product as a light yellowoil.

Step C

The iodo-product obtained from Step B above (2.2 g, 8.8 mmol) wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (10.4 mL, 17.7 mmol) was addeddropwise. After 20 min, cooling bath was removed. Reaction was continuedfor 2.5 h, and quenched with H₂O (20 mL). The aqueous mixture wasstirred overnight and separated. The aqueous layer was extracted withether (30 mL). The combined organic layers were washed with brine, driedby Na₂SO₄, and filtered through a Celite pad. Removal of solvent gave1.10 g (100%) of 3-butylfuran as a reddish-yellow oil.

Step D

3-Butylfuran (1.1 g, 8.8 mmol), obtained from Step C above, wasdissolved in 60 mL of ether, and stirred in a −78° C. bath. A 1.7 Msolution of t-butyllithium in pentane (6.0 mL, 10.2 mmol) was addeddropwise along the side wall of the flask. The mixture was stirred for 3h from −78° C. to 0° C., and continued for 1 h at room temperature. Asolution of N,N′-dimethylforamide (1.1 mL, 14.23 mmol) was added.Reaction was continued overnight, and quenched with a saturated NH₄Claqueous solution. The two layers were separated, the aqueous layer wasextracted with CH₂Cl₂ (30 mL×2). The combined organic layers were washedwith brine, dried with Na₂SO₄, and concentrated to an oil, which waspurified by preparative TLC (CH₂Cl₂-hexanes=1:1.5, v/v) to give 0.48 g(36%) of the aldehyde (contaminated by some 3-butyl-2-furaldehyde).

Preparative Example 34.19

Step A

3-Ethylfuran was prepared from 3-hydroxymethylfuran according toliterature procedure: J. Org. Chem., 1983, 48, 1106-1107 (the disclosureof which is incorporated herein by reference thereto).

Step B

3-Ethylfuran obtained from Step A above was converted to4-ethyl-2-furaldehyde using the procedure set forth in PreparativeExample 34.32, Step D.

Preparative Examples 35-51.21

Following the procedure set forth in Preparative Example 34 but usingthe commercially available aldehydes and Grignard reagents listed in theTable below, the amine products below were obtained.

Grignard 1. Yield Prep Ex. Aldehyde Reagent Amine 2. MH⁺ 35

EtMgBr

1. 65% 2. 154 36

EtMgBr

1. 75% 2. 180 37

EtMgBr

1. 78% 2. 170 38

EtMgBr

1. 34% 2. 204 39

EtMgBr

1. 68% 2. 150 40

EtMgBr

1. 40% 2. 220 41

EtMgBr

1. 73% 2. 154 42

EtMgBr

1. 52% 2. 220 43

EtMgBr

1. 55% 2. 180 44

EtMgBr

1. 20% 2. 204 45

EtMgBr

1. 80% 2. 166 46

EtMgBr

1. 35% 2. 220 47

i-PrMgBr

1. 20% 2. 150 48

EtMgBr

1. 77% 2. [M—NH₂]⁺ = 149 49

EtMgBr

1. 77% 2. 172 50

EtMgBr

1. 78% 2. [M—NH₂]⁺ = 147 51

EtLi

1. 10% 2. 116 51.2

EtMgBr

1. 37% 2. 161 51.3

EtMgBr

1. 63% 2. 216 51.4

EtMgBr

1. 71% 2. 228 51.5

EtMgBr

1. 89% 2. 168 51.6

EtMgBr

1. 20% 2. 228 51.8

EtMgBr

1. 36% 2. 222 51.10

1. 95% 2. 152.1 51.11

EtMgBr

1. 61% 2. 138.1 NH⁺—H₂O 51.12

EtMgBr

1. 70% 2. 184.1 51.18

EtMgBr

1. 42% 2. 147 [M—NH₂]⁺ 51.19

EtMgBr

1. 67% 2. 204 51.20

EtMgBr

1. 33% 2. 188 51.21

t-BuLi

1. 7% 51.22

t-BuLi

1. 20% 2. 205(M—NH₂)⁺

Preparative Examples 51.25-51.31

Following the procedure set forth in Example 34 but using thecommercially available aldehydes and Grignard reagents listed in theTable below, the amine products were obtained.

Grignard Yield Prep Ex. Aldehyde Reagent Amine (%) 51.25

EtMgBr

20 51.26

77 51.27

EtMgBr

51 51.28

56 51.29

54 51.30

EtMgBr

80 51.31

10

Preparative Example 52

Step A

A mixture of 2-(trifluoroacetyl)thiophene (2 mL, 15.6 mmol),hydroxylamine hydrochloride (2.2 g, 2 eq), diisopropylethylamine (5.5mL, 2 eq) and MeOH (50 mL) was stirred at reflux for 48-72 hrs, thenconcentrated in vacuo. The residue was diluted with EtOAc, washed with10% KH₂PO₄ and dried over Na₂SO₄ (anhydrous). Filtration andconcentration afforded the desired oxime (2.9 g, 96%) which was useddirectly in Step B without further purification.

Step B

To a mixture of the product from Step A above in TFA (20 mL) was addedZn powder (3 g, 3 eq) portionwise over 30 min and stirred at roomtemperature overnight. The solid was filtered and the mixture reduced invacuo. Aqueous NaOH (2 M) was added and the mixture was extractedseveral times with CH₂Cl₂. The organic phase was dried over anhydrousNa₂SO₄, filtered and concentrated to afford the desired product (1.4 g,50%).

Preparative Examples 53-61

Following the procedure set forth in Preparative Example 52 but usingthe commercially available ketones listed in the Table below, thefollowing amines were obtained.

Prep 1. Yield (%) Example Ketone Amine 2. MH⁺ 53

1. 11 2. 128 54

1. 33 2. 142 55

1. 49 2. 156 56

1. 5 2. 154 57

1. 47 2. 174 58

1. 71 2. 190 59

1. 78 2. 191 60

1. 80 2. 190 61

1. 9 2. 156

Preparative Example 62

To a cooled (0-5° C.) suspension of L-α-(2-thienyl)glycine (0.5 g) andLiBH₄ (2M in THF, 3.8 mL) in anhydrous THF (10 mL) was slowly added aTHF (5 mL) solution of iodine (0.8 g). After stirring at roomtemperature for 15 min, the mixture was stirred at reflux overnight.After cooling to room temperature, MeOH was added dropwise until gasevolution ceased and after 30 min, the mixture was evaporated. The oilyresidue was stirred in 20 mL KOH for 4 hrs, diluted with brine andextracted with EtOAc.

The organic phase was dried over anhydrous MgSO₄, filtered andconcentrated in vacuo to afford a crude mixture. Purification by flashcolumn chromatography (50% EtOAc/CH₂Cl₂, silica) afforded the product(0.3 g, 63%, MH⁺=144).

Preparative Example 63

CeCl₃-7H₂O was dried at 140-150° C. for 22 hr. To this solid was addedTHF (80 mL, anhydrous) and after stirring for 2 hr, the suspension wascooled to −78° C. and to it was added methyl lithium over 30 min. Afterstirring for an additional 30 min 2-thiophenecarbonitrile dissolved inanhydrous THF (4.5 mL) was added and the resulting mixture stirred foran additional 4.5 hr at −78° C. Concentrated aqueous NH₃ (25 mL) wasadded and the mixture was warmed to room temperature and filteredthrough celite. The filtrate was extracted with dichloromethane, driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo to afford acrude mixture. Purification by flash column chromatography (5% MeOH,CH₂Cl₂, silica) afforded the desired product (1.2 g, 62%).

Preparative Example 64

Step A

To a solution of (D)-valinol (4.16 g, 40.3 mmol) in CH₂Cl₂ (60 mL) at 0°C. was added MgSO₄ (20 g) followed by dropwise addition of3-fluorobenzaldehyde (5.0 g, 40.3 mmol). The heterogenous solution wasstirred at 0° C. for 2 h and was allowed to warm to room temperature andstir overnight (14 h). The mixture was filtered and the drying agent waswashed with CH₂Cl₂ (2×10 mL). The filtrate was concentrated underreduced pressure to afford 8.4 g (100%) of an oil which was taken ontothe next step without further purification.

Step B

To a solution of the imine (8.4 g, 40.2 mmol) from Step A in CH₂Cl₂ (60mL) at room temperature was added Et₃N (6.2 mL, 44.5 mmol) followed bydropwise addition of TMSCl (5.7 mL, 44.5 mmol). The mixture was stirredfor 6 h at room temperature whereupon the ppt that had formed wasfiltered off and washed with CH₂Cl₂ (2×10 mL). The combined filtrate wasconcentrated under reduced pressure and was taken up in Et₂O/hexane(1:1/150 mL). The precipitate was filtered off and the filtrate wasconcentrated under reduced pressure to afford 10.1 g (89%) of theprotected imine as an oil. This material was taken onto the next stepwithout further purification.

Step C

To a solution of EtI (4.0 g, 25.6 mmol) in Et₂O (40 mL) at −78° C. wasadded t-BuLi (30.1 mL, 51.2 mmol, 1.7 M in pentane) and the mixture wasstirred for 10 min. The mixture was warmed to room temperature, stirredfor 1 h, and was recooled to −40° C. A solution of the imine (6.0 g,21.4 mmol) from Step B in Et₂O (30 mL) was added dropwise via additionfunnel to afford a bright orange mixture. The reaction mixture wasstirred for 1.5 h at −40° C. then 3M HCl (50 mL) was added and themixture was allowed to warm to room temperature. Water (50 mL) was addedand the layers were separated. The aqueous layer was extracted with Et₂O(2×30 mL) and the organic layers were combined and discarded. Theaqueous layer was cooled to 0° C. and carefully treated with solid NaOHpellets until pH=12 was attained. The aqueous layer was extracted withEt₂O (3×30 mL) and the combined layers were washed with brine (1×30 mL).The organic layer was dried (Na₂SO₄), filtered, and concentrated underreduced pressure to afford 4.8 g (94% yield) of the amine as an oil.This material was taken on crude to the next step without furtherpurification.

Step D

To a solution of amine (4.5 g, 18.8 mmol) from Step C in MeOH (80 mL) atroom temperature was added MeNH₂ (25 mL, 40% in water) followed byaddition of a solution of H₅IO₆ (14.0 g, 61.4 mmol) in H₂O (25 mL). Theheterogenous mixture was stirred for 1.5 h (until the reaction wascomplete by TLC) and the precipitate was filtered off. The resultingfiltrate was diluted with water (50 mL) and the mixture was extractedwith Et₂O (4×60 mL). The combined organic layers were concentrated to avolume of ˜30 mL whereupon 3M HCl (75 mL) was added. The mixture wasstirred overnight (12 h at room temperature) after which the mixture wasconcentrated to remove the volatiles. The aqueous layer was extractedwith Et₂O (3×40 mL) and the organic layers were discarded. The aqueouslayer was cooled to 0° C. and was carefully treated with solid NaOHpellets until pH ˜12 was reached. The aqueous layer was extracted withEt₂O (3×60 mL) and the combined organic layers were dried (MgSO₄). Theorganic layer was concentrated under reduced pressure to afford 2.8 g(97% yield) of the desired amine as an oil [MH⁺154]. This compound wasproven to be >85% pure by ¹H NMR and was used crude in the subsequentcoupling step.

Preparative Examples 65-75.10J

Following the procedure set forth in Preparative Example 64 but usingthe prepared or commercially available aldehydes, amino alcohols, andorganolithium reagents in the Table below, the optically pure amineproducts in the Table below were obtained.

Amino Organo 1. Yield (%) Prep Ex. Aldehyde Alcohol lithium Product 2.MH⁺ 65

EtLi

1. 62 2. 154 66

EtLi

1. 70 2. 154 67

1. 54 2. 166 68

1. 67 2. 166 69

EtLi

1. 67 2. 154 70

EtLi

1. 42 2. 142 71

EtLi

1. 36 2. 142 72

1. 62 2. 148 73

t-BuLi

1. 27 2. 256 74

t-BuLi

1. 15 2. 164 75

1. 7 2. 204 75.1

EtLi

1. 65 2. 123 [M—NH₂]⁺ 75.2

EtLi

1. 62 2. 123 [M—NH₂]⁺ 75.3

EtLi

1. 93 2.139 [M—NH₂]⁺ 75.4

tBuLi

1. 50 2. 167 [M—NH₂]⁺ 75.5

tBuLi

1. 48 2. 167 [M—NH₂]⁺ 75.6

EtLi

1. 97 2. 139 [M—NH₂]⁺ 75.7

iPrLi

1. 87 2. 153 [M—NH₂]⁺ 75.8

1. 94 2. 151 [M—NH₂]⁺ 75.9

EtLi

1. 75 2. 151 [M—NH₂]⁺ 75.10

tBuLi

1. 30 2. 179 [M—NH₂]⁺ 75.10A

1. 61 2. 135 [M—NH₂]⁺ 75.10B

EtLi

1. 24 2. 154 75.10C

EtLi

1. 32 2. 165 [M—NH₂]⁺ 75.10D

MeLi

1. 47 2. 137 [M—NH₂]⁺ 75.10E

iPrLi

1. 30 2. 165 [M—NH₂]⁺ 75.10F

1. 67 2. 163.0 [M—NH₂]⁺ 75.10G

EtLi

1. 24 2. 165 [M—NH₂]⁺ 75.10H

EtLi

1. 70 2. 194 75.10J

EtLi

1. 54 2.208

Preparative Examples 75.11-75.59

Following the procedure set forth in Preparative Example 64 but usingthe prepared or commercially available aldehydes, amino alcohols, andorganolithium reagents in the Table below and carrying the amine oncrude, the optically pure amine products in the Table below wereobtained.

Amino Organo Yield Prep Ex. Aldehyde Alcohol lithium Product (%) 75.11

52 75.12

50 75.13

iPrLi

57 75.14

iPrLi

54 75.15

iPrLi

58 75.16

61 75.17

EtLi

72 75.18

68 75.19

iPrLi

77 75.20

t-BuLi

15 75.21

MeLi

50 75.22

EtLi

23 75.24

EtLi

20 75.27

EtLi

65 75.28

iPrLi

61 75.29

EtLi

90 75.30

iPrLi

62 75.31

iPrLi

43 75.32

50 75.33

50 75.34

tBuLi

51 75.35

MeLi

51 75.36

tBuLi

57 75.37

tBuLi

60 75.38

EtLi

73 75.39

MeLi

48 75.41

52 75.42

EtLi

40 75.43

tBuLi

20 75.44

t-BuLi

79 75.45

iPrLi

55 75.46

tBuLi

39 75.47

iPrLi

55 75.48

34 75.49

EtLi

61 75.50

tBuLi

25 75.51

iPrLi

33 75.52

tBuLi

30 75.53

EtLi

39 75.54

38 75.55

EtLi

64 75.56

EtLi

46 75.57

EtLi

62 75.58

iPrLi

24 75.59

EtLi

70 75.60

t-BuLi

60 75.61

iPrLi

60 75.62

t-BuLi

57 75.63

EtLi

94 75.64

t-BuLi

46 75.65

t-BuLi

60 75.66

t-BuLi

15 75.67

t-BuLi

60 75.68

MeLi

60 75.69

t-BuLi

12

Preparative Example 75.75

Step A

To a solution of aldehyde (2.5 g) in ether (50 ml) at 0° C. was addedEtMgBr (4.56 ml) dropwise. The heterogenous mixture was stirred for 2 hrat 0° C. and then poured into a beaker of saturated ammonium chloride(25 ml), ice and CH₂Cl₂ (30 ml). After the biphasic mixture stirred for10 min, the organic layer was separated, washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to afford the product (2.41g, 95%)

Step B

To a solution of alcohol from Step A above (1 g) in toluene at roomtemperature was added DPPA. The mixture was cooled to 0° C. and DBU wasadded and let stir for 12 hr at room temperature. The layers wereseparated and the organic layer was washed with water, 1N HCl and driedover Na₂SO₄, filtered, and concentrated in vacuo. Purified bypreparative plate chromatography (hexane/EtOAc 20/1) to give the product(840 mg, 75%).

Step C

To a solution of azide (730 mg) from Step B above in THF (7 ml) wasadded PPh₃ (1 g). The heterogenous solution was stirred for 12 hr,whereupon water (1.5 ml) was added. The mixture was refluxed overnight,cooled to room temperature and concentrated in vacuo. Ether and 1N HClwere added to the residue. The aqueous layer was cooled to 0° C.,basified with NaOH pellets and extracted with ether. The ether layer wasdried over MgSO₄, filtered, and concentrated in vacuo to afford theproduct (405 mg, 62%).

Step D

To a solution of azide in THF at −10° C. was added LiAlH₄ portionwise.The heterogenous solution was stirred at room temperature for 1 hr andthen refluxed for 4 hr. The solution was cooled to 0° C. and water, 2MNaOH and ether were added to the reaction. The mixture was filteredthrough a celite pad. The filtrate was treated with 3N HCl. The aqueouslayer was cooled to 0° C., basified with NaOH pellots and extracted withether. The ether layer was dried over MgSO₄, filtered, and concentratedin vacuo to afford the product.

Preparative Example 75.76-75.90

Following a similar procedure set forth in Preparative Example 75.75,and using the reduction procedure indicated, the following amines wereobtained.

Prep Ex. Aldehyde Reducing Step Product % Yield 75.76

D

43 75.77

C

36 75.78

D

32 75.79

C

42 75.80

D

56 75.81

D

35 75.82

C

13 75.83

C

42 75.84

C

39 75.85

C

26 75.86

C

25 75.87

C

14 75.88

C

49 75.89

C

34 75.90

C

44 75.92

C

74 75.93

C

81

Preparative Example 75.200

If one were to follow a similar procedure as that in Preparative Example64, but using the aldehyde from Preparative Example 1004A andcyclopentyllithium instead of ethyllithium, the title aldehyde could beprepared.

Preparative Example 75.201

If one were to follow a similar procedure as in Preparative Example75.200, but using 5-methylfuranaldehyde instead of the aldehyde fromPreparative Example 1004A, the title aldehyde could be prepared.

Preparative Example 76

The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1996, 39, 3319-3323 (the disclosure of whichis incorporated herein by reference thereto).

Preparative Example 76.1

Step A

To a solution of amine from Preparative Example 75.90 (2.22 g) in CH₂Cl₂(50 ml) at 0° C. was added TEA (3.03 ml) followed by BOC₂O (2.85 g). Theheterogenous mixture was allowed to stir at room temperature overnight.10% Citric acid was added to the reaction and the layers were separated.The organic layer was washed with saturated sodium bicarbonate, brineand dried with Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was purified by flash column chromatography (Hex/EtOAc 10:1) toafford 2.7 g of an oil (81%).

Step B

Following the procedure from Preparative Example 13.4, Step A, but usingthe product from Step A above (450 mg) and 3-thiophene boronic acid (284mg), the product was prepared (325 mg, 71%).

Step C

To the product from Step B (325 g) was added 4M HCl in dioxane (1.31 ml)and let stir for 1 hr. The reaction was concentrated in vacuo and takenup in CH₂Cl₂ and concentrated in vacuo again. This procedure wasrepeated 5 times to afford a semisolid (89%).

Preparative Example 76.2-76.3

Following the procedures set forth in Preparative Example 76.1, butusing the commercially available boronic acids, the indicated amineswere prepared.

Prep Yield Ex. Boronic Acid Product (%) 76.2

70 76.3

35

Preparative Example 76.10

Step A

The product from Preparative Example 75.75, Step A (2.5 g) was reactedvia the Preparative Example 13.11, Step B to give the ketone (1.93 g,78%).

Step B

To a solution of ketone from Step A above (500 mg) in THF (5 ml) at 0°C. was added S-2-methyl-CBS-oxazaborolidine (0.98 ml) dropwise followedby BH₃.Me₂S (1.48 ml). The mixture was stirred at 0° C. for 2 hr and wasallowed to warm to room temperature and stir overnight. The mixture wascooled to 0° C. and treated with MeOH (10 ml). After stirring for 20min, the reaction was concentrated in vacuo. The residue was dissolvedin CH₂Cl₂ and washed with 1M HCl, saturated sodium bicarbonate, waterand brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude material was purified by preparative plate chromatography(Hex/EtOAc 4:1) to afford 650 mg of an oil (89%).

Step C

The chiral alcohol from Step B above was reacted via the PreparativeExample 75.75 Step B to give the azide.

Step D

The azide from Step C above was reacted via the Preparative Example75.75 Step C to give the amine product.

Preparative Example 76.11

The desired compound was prepared as in Preparative Example 76.10, butusing the R-2-methyloxazaborolidine in step B.

Preparative Example 77

The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1996, 39, 3319-3323 (the disclosure of whichis incorporated herein by reference thereto).

Preparative Example 78

The desired compound was prepared according to methods previouslydescribed in Chem. Pharm. Bull. 1991, 39,181-183 (the disclosure ofwhich is incorporated herein by reference thereto).

Preparative Example 78.1

The desired compound was prepared according to methods previouslydescribed in J. Organometallic Chem. 1998, 567, 31-37 (the disclosure ofwhich is incorporated herein by reference thereto).

Preparative Example 79

The desired compound was prepared according to methods previouslydescribed in Chem. Pharm. Bull. 1991, 39, 181-183 (the disclosure ofwhich is incorporated herein by reference thereto).

Preparative Example 80

The desired compound was prepared according to methods previouslydescribed in (a) Synthesis 1987, 998-1001, (b) Synthesis 1996, 641-646,and (c) J. Med. Chem. 1991, 34, 2176-2186 (the disclosures of eachreference being incorporated herein by reference thereto).

Preparative Example 81

The desired compound was prepared according to methods previouslydescribed in (a) Synthesis 1987, 998-1001, (b) Synthesis 1996, 641-646and (c) J. Med. Chem. 1991, 34, 2176-2186 (the disclosures of eachreference being incorporated herein by reference thereto).

Preparative Example 82

The desired compound was prepared according to methods previouslydescribed in J. Med. Chem. 1988, 31, 2176-2186 (the disclosure of whichis incorporated herein by reference thereto).

Preparative Example 83

To a solution of carboxylic acid (1.5 g, 7.89 mmol) in H₂O/acetone(1:10/12 mL total) at 0° C. was added Et₃N (1.43 mL, 10.3 mmol) followedby addition of ethyl chloroformate (0.83 mL, 8.68 mmol). The resultingmixture was stirred for 30 min after which a solution of NaN₃ (0.77 g,11.8 mmol) in H₂O (2 mL) was added dropwise. The resultant heterogenousmixture was stirred for 1 h at 0° C., then cold water (5 mL) and Et₂O(10 mL) were added. The layers were separated and the aqueous layer wasextracted with Et₂O (2×10 mL). The organic layers were combined, toluene(20 mL) was added, and the organic layers were dried (MgSO₄) andconcentrated under reduced pressure to a volume of 20 mL. t-BuOH (5 mL)was added and the mixture was refluxed for 12 h. The mixture wasconcentrated under reduced pressure and the crude residue was taken upin 3M HCl (30 mL) and was heated at reflux for 12 h. The mixture wascooled to room temperature and extracted with Et₂O (3×15 mL). Theaqueous layer was cooled to 0° C. and solid NaOH pellets were addeduntil pH ˜12 was reached. The aqueous layer was extracted with Et₂O(3×30 mL) and the combined organic layers were dried (MgSO₄) andconcentrated under reduced pressure to afford 0.78 g (61% yield) of anoil [MH⁺162]. This material was used without further purification.

Preparative Example 84

The corresponding cyclopropyl analog was prepared according to theprocedure outlined in Preparative Example 83.

Preparative Example 85

The corresponding cyclohexyl analog was prepared according to theprocedure outlined in Preparative Example 83.

Preparative Example 86

The desired compound was prepared according to methods previouslydescribed in J. Org. Chem. 1978, 43, 892-898 (the disclosure of which isincorporated herein by reference thereto).

Preparative Example 88.2

Step A

2-Methylthiophene (3 g) was dissolved in THF and cooled to −40° C.N-butyllithium (2.5M in hexane, 12.24 ml) added dropwise and let stir at−40° C. for 30 min. CuBr.(CH₃)₂S (6.29 g) added and let warm to −25° C.where the trifluoroaceticanhydride (4.32 ml) was added. The reaction wasstirred at −15° C. over the weekend. The reaction was quenched withsaturated ammonium chloride and extracted with EtOAc. The organic layerwashed with brine, dried with MgSO₄, filtered and concentrated in vacuoto give 4.59 g of an oil (78%).

Step B

The product from Step A (4.58 g), hydroxylamine hydrochloride (3 g),sodium acetate (4.4 g), EtOH (75 ml) and H₂O (7.5 ml) were combined andheated to 75° C. overnight. The reaction was concentrated in vacuo,taken up 1N HCl, extracted with ether, dried with MgSO₄, filtered andconcentrated in vacuo to give 4.58 g of the product (93%, MH+=210).

Step C

The product from Step B above (4.5 g) was dissolved in TFA (40 ml) andcooled to 0° C. Zn powder (4.2 g) was added portionwise and let reactionwarm to room temperature and stir overnight. The reaction wasconcentrated in vacuo, taken up in 1N NaOH, extracted with ether, driedwith MgSO₄, filtered and concentrated in vacuo to give 3.43 g of theproduct (80%).

Preparative Example 89

To a solution of KH (0.45 g, 11.3 mmol) in THF (15 mL) at roomtemperature was added amine hydrochloride (0.85 g, 5.1 mmol) portionwiseto afford a heterogenous reaction mixture. The mixture was allowed tostand overnight (12 h) and Mel (0.32 mL, 5.1 mmol) was added dropwise.The mixture was stirred for 6 h after which the mixture was carefullypoured into cold brine (125 mL). The mixture was extracted with Et₂O(3×25 mL) and the organic layers were combined. The organic layer wasdried (Na₂SO₄), filtered, and concentrated under reduced pressure toafford the crude product as an oil. This material was carried on crudeto the coupling step without further purification or characterization.

Preparative Example 89.1

To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added(R)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture.The mixture was allowed to stand overnight (18 hr) and then Mel (1.59ml) was added dropwise. The mixture was stirred for 4 hr after whichbrine was added. Extracted with ether, dried with K₂CO₃, filtered andconcentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 89.2

To a solution of KH (1.1 g) in THF (20 ml) at room temperature was added(S)-2-amino-1-butanol 48 ml) dropwise to afford a heterogenous mixture.The mixture was allowed to stand overnight (18 hr) and then MeI (1.59ml) was added dropwise. The mixture was stirred for 4 hr after whichbrine was added. Extracted with ether, dried with K₂CO₃, filtered andconcentrated in vacuo to afford 1.75 g of an oil.

Preparative Example 90

The corresponding cis analog was prepared in an analogous fashionutilizing the procedure described in Preparative Example 89. Thismaterial was also used without further purification.

Preparative Example 91

The desired compound was prepared according to methods previouslydescribed in J. Org. Chem. 1987, 52, 4437-4444 (the disclosure of whichis incorporated herein by reference thereto).

Preparative Example 92

The desired compound was prepared according to methods previouslydescribed in Bull. Chem. Soc. Jpn. 1962, 35, 11-16 (the disclosure ofwhich is incorporated herein by reference thereto).

Preparative Example 93

The desired amine was prepared from the corresponding ketone accordingto standard methods previously described in (a) Synthesis 1987,998-1001, (b) Synthesis 1996, 641-646 and (c) J. Med. Chem. 1991, 34,2176-2186 (the disclosures of each being incorporated herein byreference thereto).

Preparative Example 94

The desired amine was prepared from the corresponding ketone accordingto standard methods previously described in (a) Synthesis 1987,998-1001, (b) Synthesis 1996, 641-646 and (c) J. Med. Chem. 1991, 34,2176-2186 (the disclosures of each being incorporated herein byreference thereto).

Preparative Example 95

Step A

Lithium hexamethyldisilylazide (34 mL, 1M in THF) was added dropwise toa −78° C. THF (20 mL) solution of isobutyronitrile (2.8 mL). After 40min, cyclopropylmethylbromide (5 g) was added and the mixture warmed toand stirred at 25° C. overnight. After cooling to 0° C., 1M HCl (aq) wasadded and the mixture was extracted with diethyl ether, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo at 0° C. to givethe desired product (4.5 g).

Step B

Methyl Lithium (17 mL, 1.4 M in Et₂O) was added to the product from StepA above (1.5 g) in Et₂O (anhydrous) at 0° C. The mixture was stirred at0-25° C. overnight, then diluted with 3M HCl (aq), extracted withCH₂Cl₂, dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo at0° C. and used directly in Step C.

Step C

The product from Step B above was added to a slurry of NaBH₄ (1.4 g) inisopropanol (50 mL) at 0° C., then the mixture was stirred at reflux for8 hr and at room temperature for 48 hrs. Water was added and the mixturewas stirred for 30 min, then extracted with diethyl ether, dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue wasdiluted with CH₂Cl₂ and extracted with 3M HCl. The organic phase wasdiscarded and the aqueous phase was basified with NaOH (aq) andextracted with CH₂Cl₂. Drying over anhydrous Na₂SO₄, filtering, andconcentration in vacuo gave the desired compound (0.5 g).

Preparative Example 96

Step A

2-Thiophenecarbonyl chloride (2.0 mL, 18.7 mmol) was dissolved in 100 mLdichloromethane. After addition of diisopropylethylamine (4.1 mL, 23.4mmol) and Boc-piperazine (3.66 g, 19.7 mmol), the mixture was stirredfor 4 h at room temperature. The resulting mixture was put into water(500 mL) and acidified with 3N HCl to pH˜1. Extraction withdichloromethane (2×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in the next step without anyfurther purification.

¹H NMR (300 MHz, d₆-DMSO) 1.60 (s, 9H), 3.29 (dd, 4H), 3.69 (dd, 4H),7.23 (dd, 1H), 7.49 (d, 1H), 7.79 (d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 2 h, the reactionmixture was put into 1N sodium hydroxide (400 mL). Extraction withdichloromethane (2×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.81 (dd, 4H), 3.63 (dd, 4H),7.21 (dd, 1H), 7.46 (d, 1H), 7.82 (d, 1H).

Step C

The crude material (3.50 g, 17.8 mmol) from Step B was dissolved indichloromethane (100 mL). After addition of diisopropylethylamine (18.7mL, 107 mmol), 3-nitrosalicylic acid (3.3 g, 18.0 mmol), and PyBrOP(10.4 g, 22.3 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (200 mL).Extraction with dichloromethane (2×200 mL) removed all PyBrOPby-products. The aqueous phase was acidified with 3N HCl andsubsequently extracted with dichloromethane (3×100 mL). The combinedorganic phases of the acidic extraction were dried over sodium sulfate,concentrated, and finally purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (2.31 g,34% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.90 (m, 8H),7.10-8.20 (m, double signals due to E/Z-isomers, 6H), 10.82 (s, 1H).

Step D

The nitro-compound (2.3 g, 6.4 mmol) from Step C was dissolved inmethanol (50 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (1.78 g,84%). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.90 (m, 8H), 7.22 (m, 2H), 7.55(d, 1H), 7.71 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 10.85 (bs, 1H).

Preparative Example 97

Step A

Picolinic acid (3.0 g, 24.3 mmol) was suspended in SOCl₂ (15 mL). Afteraddition of dimethylformamide (5 drops), the reaction mixture wasstirred for 4 hours. Evaporation of the solvent yielded thecorresponding acid chloride as HCl-salt. Without any furtherpurification, the solid was suspended in 120 mL dichloromethane. Afteraddition of diisopropylethylamine (12.7 mL, 73 mmol) and Boc-piparazine(4.8 g, 25.5 mmol), the reaction was stirred over night at roomtemperature. The resulting mixture was put into water (500 mL) andextracted with dichloromethane (2×100 mL). Drying over sodium sulfateresulted in sufficiently pure product that was used in Step B withoutany further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.63 (s, 9H), 3.21(dd, 4H), 3.61 (dd, 4H), 7.57 (dd, 1H), 7.63 (d, 1H), 7.98 (dd, 1H),8.70 (d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 2 days, thereaction mixture was put into 1N sodium hydroxide (400 mL). Extractionwith dichloromethane (2×100 mL) and drying over sodium sulfate resultedin sufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.77 (dd, 2H), 2.83 (dd, 1H),3.38 (dd, 2H), 3.64 (dd, 1H), 7.58 (dd, 1H), 7.62 (d, 1H), 8.00 (dd,1H), 8.67 (d, 1H).

Step C

The crude material (1.35 g, 7.06 mmol) from Step B was dissolved indichloromethane (50 mL). After addition of diisopropylethylamine (3.7mL, 21.2 mmol), 3-nitrosalicylic acid (1.36 g, 7.41 mmol), and PyBrOP(3.62 g, 7.77 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (300 mL).Extraction with dichloromethane (2×100 mL) removed any PyBrOP products.The aqueous phase was acidified with 3N HCl. Adjustment of the pH withsaturated sodium carbonate solution to almost neutral crushed thedesired compound out of solution. The aqueous phase was subsequentlyextracted with dichloromethane (3×100 mL). The combined organic layersof the neutral extraction were dried over sodium sulfate, concentrated,and finally purified by column chromatography(dichloromethane/methanol=20/1) to yield the desired product (1.35 g,16% over 3 steps). ¹H NMR (300 MHz, d₆-DMSO) 3.30-3.95 (m, 8H), 7.22 (m,1H), 7.61 (m, 1H), 7.73 (d, 2H), 8.03 (m, 1H), 8.17 (m, 1H), 8.69 (m,1H), 10.82 (s, 1H).

Step D

The nitro-compound (1.35 g, 3.79 mmol) from Step C was dissolved inmethanol (60 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol=20/1) to yield the desired product (1.10 g,89%). ¹H NMR (300 MHz, d₆-DMSO) 3.50-3.85 (m, 8H), 6.47 (dd 1H), 6.74(m, 2H), 7.59 (dd, 1H), 7.71 (d, 1H), 8.04 (dd, 1H), 8.68 (d, 1H).

Preparative Example 98

Step A

1-Methyl-2-pyrrolecarboxylic acid (2.5 g, 20.0 mmol) was dissolved indichloromethane (50 mL). After addition of PyBrOP (16.3 g, 35.0 mmol),diisopropylethylamine (14.0 mL, 73.0 mmol) and Boc-piparazine (5.5 g,30.0 mmol), the reaction was stirred over night at room temperaturebefore being put into 1N sodium hydroxide (200 mL). Extraction withdichloromethane (2×100 mL) removed all PyBrOP by-products. The aqueousphase was acidified with 3N HCl. Adjustment of the pH with saturatedsodium carbonate solution to almost neutral precipitated the desiredcompound. The aqueous phase was subsequently extracted withdichloromethane (3×100 mL). The combined organic phases of the neutralextraction were dried over sodium sulfate. Removal of the solventresulted in sufficiently pure product that was used in Step B withoutany further purification. ¹H NMR (300 MHz, d₆-DMSO) 1.59 (s, 9H) 3.21(dd, 4H), 3.61 (dd, 4H), 3.74 (s, 3H), 6.11 (dd, 1H), 6.33 (d, 1H), 7.01(d, 1H).

Step B

The crude material from Step A was dissolved in trifluoroaceticacid/dichloromethane (75 mL, 4/1). After stirring for 3 h, the reactionmixture was put into 1N sodium hydroxide (400 mL). Extraction withdichloromethane (3×100 mL) and drying over sodium sulfate resulted insufficiently pure product that was used in Step C without any furtherpurification. ¹H NMR (300 MHz, d₆-DMSO) 2.79 (dd, 4H), 3.62 (dd, 4H),3.76 (s, 3H), 6.11 (dd, 1H), 6.37 (d, 1H), 6.96 (d, 1H).

Step C

The crude material (3.15 g, 16.3 mmol) from Step B was dissolved indichloromethane (100 mL). After addition of diisopropylethylamine (8.5mL, 49.0 mmol), 3-nitrosalicylic acid (3.13 g, 17.1 mmol), and PyBrOP(9.11 g, 19.6 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (400 mL).Extraction with dichloromethane (2×100 mL) removed all PyBrOP products.The aqueous phase was then carefully acidified with 3N HCl until thecolor of the solution changes from orange to yellow and the desiredcompound crashed out of solution. The aqueous phase was subsequentlyextracted with dichloromethane (3×100 mL). The combined organic layersof the acidic extraction were dried over sodium sulfate and concentratedin vacuo to yield the desired product. ¹H NMR (300 MHz, d₆-DMSO)3.35-3.85 (m, 8H), 3.79 (s, 3H), 6.13 (dd, 1H), 6.45 (d, 1H), 7.01 (s,1H), 7.22 (dd, 1H), 7.70 (d, 1H), 8.16 (d, 1H), 10.83 (s, 2H).

Step D

The crude nitro-compound from Step C was suspended in methanol (60 mL)and stirred with 10% Pd/C under a hydrogen gas atmosphere over night.The reaction mixture was filtered through Celite and washed thoroughlywith methanol. The filtrate was concentrated in vacuo and purified bycolumn chromatography (dichloromethane/methanol=10/1) to yield thedesired product (2.61 g, 40% for 4 steps). ¹H NMR (300 MHz, d₆-DMSO)3.45-4.80 (m, 8H), 3.79 (s, 3H), 6.17 (dd, 1H), 6.45 (m, 2H), 6.78 (m,2H), 7.01 (d, 1H).

Preparative Example 99

Step A

2-Bromopyridine N-oxide hydrochloride (1.13 g, 5.37 mmol) andBoc-piperazine (1.50 g, 8.06 mmol) were heated to 80° C. in pyridine (10mL) over night. The reaction mixture was put into water (300 mL) andthen extracted with dichloromethane (2×100 mL). The combined organicphases were dried over sodium sulfate, concentrated, and finallypurified by column chromatography (dichloromethane/methanol=10/1) toyield the desired product (500 mg, 33%).

¹H NMR (300 MHz, d-CDCl₃) 1.60 (s, 9H), 3.46 (dd, 4H), 3.78 (dd, 4H),6.99 (m, 2H), 7.37 (dd, 1H), 8.33 (d, 1H).

Step B

The purified product (500 mg, 1.79 mmol) was stirred for 30 min with 4NHCl/dioxane (15 mL). Evaporation of the solvent yielded the crude amine(465 mg) as multiple HCl-salt which was used in Step C without anyfurther purification.

¹H NMR (300 MHz, d₆-DMSO) 3.38 (m, 4H), 4.81 (m, 4H), 7.34 (dd, 1H),7.55 (d, 1H), 7.86 (dd, 1H), 8.55 (d, 1H).

Step C

The crude material (370 mg, 1.48 mmol) from Step B was suspended indichloromethane (20 mL). After addition of diisopropylethylamine (2.6mL, 14.8 mmol), 3-nitrosalicylic acid (406 mg, 2.22 mmol), and PyBrOP(1.21 g, 2.59 mmol), the mixture was stirred over night at roomtemperature before being put into 1N sodium hydroxide (50 mL).Extraction with dichloromethane (2×50 mL) removed all PyBrOP products.The aqueous phase was then carefully acidified (pH ˜4-5) with 3N HCl andextracted with dichloromethane (3×50 mL). The combined organic layers ofthe acidic extraction were dried over sodium sulfate, concentrated invacuo and purified by column chromatography(dichloromethane/methanol=10/1) to yield the desired product (330 mg,65%).

LCMS calculated: 344.1, found: (M+1)⁺345.1

Step D

Sodium hydrosulfite (1.05 g) was dissolved in water (3.0 mL) to yield a1.5N solution. Addition of dioxane (3.0 mL) was followed by injection ofconc. ammonium hydroxide (0.60 mL, yields a 1.0N concentration). Afteraddition of the nitro-compound (100 mg, 0.29 mmol), the reaction mixturewas stirred for 0.5 h. Subsequently, the solvent was removed and theresidue suspended in dichloromethane/methanol (10/1). Filtration throughCelite removed most of the salts. Final purification by columnchromatography (dichloromethane/methanol=5/1) yielded the desiredproduct (68 mg, 75%).

LCMS calculated: 314.14, found: (M+1)⁺315.1

Preparative Example 100

Step A

4-Bromopyridine hydrochloride (3.0 g, 15.4 mmol) was dissolved in water(15 mL). After addition of N-benzylpiperazine (14.8 mL, 85.0 mmol) and500 mg copper sulfate, the reaction mixture was heated overnight to 140°C. The resulting product was extracted with ether (5×75 mL), dried oversodium sulfate and concentrated. Final purification by columnchromatography (dichloromethane/methanol/NH₄OH=10/1/0.1) yielded thedesired product (2.16 g, 55%). ¹H NMR (300 MHz, d-CDCl₃) 2.68 (dd, 4H),3.45 (dd, 4H), 6.76 (d, 2H), 7.40 (m, 5H), 8.38 (d, 2H).

Step B

The benzylamine (2.16 g, 8.54 mmol) from Step A, ammonium formate (2.71g, 43.0 mmol) and Pd(C) (10%, 1.0 g) was suspended in methanol (50 mL)and refluxed for 3 h. The palladium was filtered off and the filtratewas concentrated. The sufficiently pure product was used in Step Cwithout any further purification. ¹H NMR (300 MHz, d-CDCl₃) 2.48 (bs,1H), 3.13 (dd, 4H), 3.41 (dd, 4H), 7.78 (d, 2H), 8.39 (d, 2H).

Step C

The crude material (1.15 g, 7.06 mmol) from Step B was dissolved indichloromethane (50 mL). After addition of diisopropylethylamine (4.7mL, 42.4 mmol), 3-nitrosalicylic acid (1.94 g, 10.6 mmol), and PyBrOP(5.78 g, 12.3 mmol), the resulting mixture was stirred over night atroom temperature before being put into 1N sodium hydroxide (300 mL).Extraction with dichloromethane (2×100 mL) removed all PyBrOP products.The aqueous phase was carefully acidified to pH ˜5-6 with 3N HCl andextracted with dichloromethane (3×100 mL). The combined organic layersof the neutral extraction were dried over sodium sulfate, concentrated,and finally purified by column chromatography(dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product(850 mg, 37% for 2 steps).

Step D

The nitro-compound (850 mg, 2.59 mmol) from Step C was dissolved inmethanol (40 mL) and stirred with 10% Pd/C under a hydrogen gasatmosphere over night. The reaction mixture was filtered through Celiteand washed thoroughly with methanol. Finally, the filtrate wasconcentrated in vacuo and purified by column chromatography(dichloromethane/methanol/NH₄OH=10/1/0.1) to yield the desired product(650 g, 84%). ¹H NMR (300 MHz, d₆-DMSO) 3.40-3.75 (bm, 8H), 6.49 (dd,1H), 6.76 (m, 2H), 6.93 (d, 2H), 8.28 (d, 2H).

Preparative Example 101

Step 1

N,N′-Dibenzyl-ethane-1,2-diamine (20 mL, 0.0813 mol), triethylamine(22.66 mL, 0.1626 mol) and benzene (100 mL) were combined in a roundbottom flask. A solution of 2,3-dibromo-propionic acid ethyl ester(11.82 mL, 0.0813 mol) in benzene (50 mL) was added dropwise. Thesolution was refluxed over night and monitored by TLC (20% ethylacetate/hexane). The reaction was cooled to room temperature, thenfiltered and washed with benzene. The filtrate was concentrated thenpurified by column chromatography (15% ethyl acetate/hexane). Theproduct was isolated as an oil (25.42 g, 0.0752 mol, 92%). MS:calculated: 338.20, found: 339.2

¹H NMR (300 MHz, CDCl₃) 1.23 (t, 3H), 2.48 (m, 3H), 2.62 (m, 1H), 2.73(m, 1H), 3.07 (m, 1H), 3.30 (m, 1H), 3.42 (d, 1H), 3.56 (m, 2H), 3.91(d, 1H), 4.17 (m, 2H), 7.27 (m, 10H).

Step 2

In a Parr shaker vessel, the ester (25.43 g, 0.075 mol) and methanol(125 mL) were combined. The vessel was purged with argon and palladiumcatalyst (5% on carbon, 2.5 g) was added. The system was shaken under anatmosphere of hydrogen overnight. TLC (20% ethyl acetate/hexane)indicated that reaction was complete. The reaction mixture was filteredthrough a pad of Celite and washed with methanol. The filtrate wasconcentrated and the product isolated as a solid (11.7 g, 0.074 mol,98%).

MS: calculated: 158.11, found: 159.2 ¹H NMR (300 MHz, CDCl₃) 1.27 (t,3H), 2.70 (m, 4H), 2.96 (m, 1H), 3.13 (dd, 1H), 3.43 (dd, 1H), 4.18 (m,2H).

Preparative Example 102

Piperazine-2-carboxylic acid ethyl ester (3.11 g, 0.0197 mol),diisopropylethylamine (5.15 mL, 0.0296 mol) and methylene chloride (200mL) were combined in aground bottom flask. While stirring at roomtemperature, a solution of N,N-dimethylcarbamoyl chloride (1.81 mL,0.0197 mol) in methylene chloride (20 mL) was added dropwise. Thereaction was stirred for one hour. After this time the reaction wasconcentrated and carried on to the next step without furtherpurification. (99% yield).

MS: calculated: 229.14, found: 230.1

¹H NMR (300 MHz, CDCl₃) 1.30 (t, 3H), 2.85 (s, 6H), 3.10 (m, 3H), 3.31(m, 2H), 3.60 (m, 2H), 4.21 (q, 2H).

Preparative Example 103-104

Following the procedure described for Preparative Example 102, theProducts listed in the table below were prepared using the commerciallyavailable chloride shown and piperazine-2-carboxylic acid ethyl esterfrom Preparative Example 101.

Ex- am- 1. Yield (%) ple Chloride Product 2. (M + 1)⁺ 103

1. 99 2. 237.1 104

1. 62 2. 253.1

Preparative Example 105

Step 1

3-Nitrosalicylic acid (3.61 g, 0.0197 g), DCC (2.03 g, 0.0099 mol) andethyl acetate (130 mL) were combined in a round bottom flask and stirredfor 15 min. 4-Dimethylcarbamoyl-piperazine-2-carboxylic acid ethyl ester(4.51 g, 0.0197 g) was added, and the reaction was stirred for 72 hours.The reaction mixture was concentrated then dissolved in dichloromethane.The organic phase was washed once with 0.1N sodium hydroxide. Theaqueous phase was back extracted once with dichloromethane. The aqueousphase was acidified and wash three times with ethyl acetate. The aqueousphase was concentrated and purified by column chromatography (5%methanol/DCM).

MS: calculated: 394.15, found: 395.0

¹H NMR (300 MHz, CDCl₃) 1.32 (t, 3H), 2.86 (m, 7H), 3.15 (m, 1H), 3.51(m, 4H), 4.24 (m, 3H), 7.15 (m, 1H), 7.66 (m, 1H), 8.20 (m, 1H), 10.86(bs, 1H).

Step 2

4-Dimethylcarbamoyl-1-(2-hydroxy-3-nitro-benzoyl)-piperazine-2-carboxylicacid ethyl ester (0.80 g, 0.002 mol) and methanol (50 mL) were combinedin a round bottom flask. The system was purged with argon. To thesolution was added 5% palladium on carbon (˜100 mg). The flask waspurged with hydrogen and stirred overnight. The reaction was filteredthrough a pad of celite and washed with methanol. The material wasconcentrated then purified by column chromatography (6% methanol/DCM).Isolated product (0.74 g, 0.002 mol, 100%).

MS: calculated: 364.17, found: 365.1

¹H NMR (300 MHz, CDCl₃) 1.27 (t, 3H), 2.85 (m, 8H), 3.18 (1H), 3.45 (m,3H), 4.19 (m, 3H), 3.90 (m, 3H)

Step 3

1-(3-Amino-2-hydroxy-benzoyl)-4-dimethylcarbamoy-piperazine-2-carboxylicacid ethyl ester (0.74 g, 0.002 mol) was suspended in a solution ofdioxane (10 mL) and water (10 mL). Lithium hydroxide (0.26 g, 0.0061mol) was added and the mixture stirred for two hours. The solution wasacidified to pH=6 with 3N HCl then extracted with butanol. The extractswere combined, dried over sodium sulfate and concentrated.

MS: calculated: 336.14, found: 337.1

¹H NMR (300 MHz, CD₃OD) 2.86 (m, 7H), 3.23 (m, 3H), 3.54 (m, 3H), 6.92(m, 2H), 7.23 (m, 1H).

Preparative Example 106-107

Following the procedure described for Example 105, the Products listedin the table below were prepared using the amine from the PreparativeExample indicated and 3-nitrosalacylic acid.

1. Yield (%) 2. (M + 1)⁺ Example Aniline Product 3. Note 106 103

1. 91 2. Not observed 3. Rainey nickel used in Step 2 107 104

1. 24 2. 360.0 3. For Step 1 used PyBrop/DIEA in DCM

Preparative Example 108

Step A

3-Nitrosalicylic acid (1.0 g, 5.5 mmol) was dissolved in ethyl acetate(20 mL). 1,3-Dicyclohexylcarbodiimide (0.568 g, 2.8 mmol) was added andthe mixture was stirred for approximately 10 minutes and cooled to 0° C.During this time a precipitate formed. Azetidine (0.39 mL, 5.8 mmol) wasadded and the reaction was stirred overnight and allowed to warm to roomtemperature. After this time the reaction was cooled to 0° C. andfiltered. The collected solid was washed with chilled ethyl acetate. Thefiltrate was concentrated and purified by column chromatography (80%EtOAc/Hex) to give the product (476 mg, 39.0%).

¹H NMR (300 MHz, CDCl₃) δ2.40 (m, 2H), 4.38 (m, 4H), 6.97 (m, 1H), 7.62(d, 1H), 8.12 (d, 1H), 12.88 (m, 1H) ppm.

Step B

The nitro compound (0.48 g, 2.1 mmol) from Preparative Example 32 Step Awas dissolved in methanol (25 ml) and stirred with 10% Pd/C under ahydrogen gas atmosphere overnight. The reaction mixture was filteredthrough celite, the filtrate concentrated in vacuo to give the product(344 mg, 90%). ¹H NMR (300 MHz, CDCl₃) δ2.52 (m, 2H), 4.57 (bs, 4H),6.75 (m, 1H), 6.90 (m, 2H), 12.71 (bs, 1H) ppm.

Preparative Example 109

In essentially the same manner as described in Preparative Example 108above, the morpholino-amine product was obtained.

Preparative Example 110

Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL).N,N′-Dimethylcarbamoyl chloride (1.0 mL, 0.011 mol) was added dropwiseto the solution at room temperature. The reaction was stirred for onehour. After this time 1N potassium hydroxide (200 mL) was added. Thelayers were separated and the aqueous layer was extracted three timeswith dichloromethane. The organic fractions were combined and dried oversodium sulfate. Filtration and concentration provided the product,without further purification, as an oil (1.16 g, 13%).

¹H NMR (CDCl₃, 300 MHz) 1.95 (s, 1H), 2.83 (s, 6H), 2.86 (m, 4H), 3.20(m, 4H).

MS: calculated: 157.12, found: 158.1.

Preparative Example 111

Piperazine (4.9 g, 0.057 mol) was dissolved in 1N HCl (100 mL). Asolution of phenylsulfonylchloride (1.45 mL, 0.011 mol) in acetonitrile(25 mL) was added dropwise to the solution at room temperature. Thereaction was stirred for 30 minutes. After this time the reaction wasextracted two times with ethyl acetate. The solution was then made basicwith 1N potassium hydroxide and extracted three times withdichloromethane. The dichloromethane fractions were combined and driedover magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (1.22 g, 9.4%).

¹H NMR (CDCl₃, 300 MHz) 2.94 (m, 8H), 7.56 (m, 3H), 7.76 (m, 2H).

MS: calculated: 226.08, found: 227.1.

Preparative Example 112

Piperazine (4.9 g, 0.057 mol) was dissolved in dichloromethane (100 mL).Methanesulfonyl chloride (0.85 mL, 0.011 mol) was added dropwise to thesolution at room temperature. The reaction was stirred for 30 minutes.After this time 1N potassium hydroxide (200 mL) was added. The layerswere separated and the aqueous layer was extracted three times withdichloromethane. The organic fractions were combined and dried oversodium sulfate. Filtration and concentration provided the product,without further purification, as a solid (1.07 g, 11%).

¹H NMR (CDCl₃, 300 MHz) 1.75 (s, 1H), 2.78 (s, 3H), 2.97 (m, 4H), 3.20(m, 4H).

MS: calculated: 164.06, found: 165.1.

Preparative Example 113

Step A

Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100mL). Propylisocyanate (1.51 mL, 0.0161 mol) was added to the solution atroom temperature. The reaction was stirred for over night. After thistime the reaction was diluted with 1N potassium hydroxide (200 mL) andextracted six times with dichloromethane. The organic fractions werecombined and dried over magnesium sulfate. Filtration and concentrationprovided the product as a solid.

Step B

The product of Step A above, was dissolved in a 30% trifluoroaceticacid/dichloromethane solution and stirred overnight. After this time a1N potassium hydroxide solution (200 mL) was added to the reaction. Theaqueous layer was extracted a total of six times with dichloromethane.The organic fractions were combined and dried over sodium sulfate.Filtration and concentration provided the product (1.37 g, 50%).

1H NMR (CDCl₃, 300 MHz) 0.92 (t, 3H), 1.52 (m, 2H), 2.89 (m, 4H), 3.01(s, 1H), 3.18 (m, 2H), 3.37 (m, 4H), 4.61 (bs, 1H).

MS: calculated: 171.14, found: 172.0.

Preparative Example 114

Piperazine (4.9 g, 0.0569 mol) was dissolved in 1N HCl (70 mL). Asolution of phenylchloroformate (1.43 mL, 0.0114 mol) in acetonitrile(25 mL) was added dropwise to the solution at room temperature. Thereaction was stirred for 30 minutes. After this time the reaction wasextracted two times with ethyl acetate. The solution was then made basicwith 1N potassium hydroxide and extracted three times withdichloromethane. The dichloromethane fractions were combined and driedover magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (2.12 g, 18%).

¹H NMR (CDCl₃, 300 MHz) 1.78 (s, 1H), 2.91 (m, 4H), 3.59 (m, 4H), 7.11(2H), 7.19 (m, 1H), 7.36 (m, 2H).

MS: calculated: 206.24, found: 207.1.

Preparative Example 115-117

Following the procedure described for Example 112, the Products listedin the table below were prepared using the commercially availablechloroformate shown and piperazine.

1. Yield (%) Example Chloroformate Product 2. (M + 1)⁺ 115

1. 54 2. 144.9 116

1. 17 2. 173.0 117

1. 69 2. 173.0

Preparative Example 118

Step A

Boc-Piperazine (3.01 g, 0.0161 mol) was dissolved in dichloromethane(100 mL) along with diisopropylethylamine (5.61 mL, 0.0322 mol).Benzoylchloride (1.87 mL, 0.0161 mol) was added dropwise to the solutionat room temperature. The reaction was stirred for several hours. Afterthis time the reaction was concentrated and the product was purified bycolumn chromatography (10% MeOH/DCM). Boc-Protected product was isolatedas a solid (5.21 g).

¹H NMR (CDCl₃, 300 MHz) 1.47 (s, 9H), 3.45 (m, 8H), 7.41 (m, 5H).

MS: calculated: 290.16, found: 290.8.

Step B

The product from Step A above, was dissolved in a 50% trifluoroaceticacid/dichloromethane solution and stirred overnight. After this time thereaction was diluted with 1N potassium hydroxide (200 mL) and theorganic layer was separated. The aqueous phase was then extracted sixtimes with dichloromethane. The organic fractions were combined anddried over magnesium sulfate. Filtration and concentration providedproduct (2.93 g).

¹H NMR (CDCl₃, 300 MHz) 1.92 (s, 1H), 2.87 (m, 4H), 3.52 (m, 4H), 7.39(s, 5H).

MS: calculated: 190.11, found: 191.1.

Preparative Example 119

Step A

Boc-Piperazine (3.0 g, 0.0161 mol) was dissolved in dichloromethane (100mL) along with diisopropylethylamine (3.1 mL, 0.0177 mol).N,N′-dimethylsulfamoyl chloride (1.73 mL, 0.0161 mol) was added dropwiseto the solution at room temperature. The reaction was stirred forseveral hours. After this time the reaction was diluted with water (100mL). The layers were separated and the aqueous layer was extracted sixtimes with dichloromethane. The organic fractions were combined anddried over magnesium sulfate. Filtration and concentration provided theproduct, without further purification, as a solid (4.53 g).

¹H NMR (CDCl₃, 300 MHz) 1.47 (s, 9H), 2.84 (s, 6H), 3.21 (m, 4H), 3.48(m, 4H).

MS: calculated: 293.14, found: 194.1 (M-Boc)⁺.

Step B

The product from Step A above, was dissolved in a 30% trifluoroaceticacid/dichloromethane solution and stirred overnight. After this time thereaction was diluted with water and 1N potassium hydroxide was used tomake the aqueous layer slightly basic. The aqueous layer was extracted atotal of seven times with dichloromethane. The organic fractions werecombined and dried over sodium sulfate. Filtration and concentrationprovided the product (2.96 g).

¹H NMR (CDCl₃, 300 MHz) 2.03 (s, 1H), 2.83 (s, 6H), 2.92 (m, 4H), 3.23(m, 4H).

MS: calculated: 193.09, found: 194.1.

Preparative Example 120

In essentially the same manner as that described in Preparative Example105, Step 1, using 3-nitrobenzoic acid instead of 3-nitrosalicylic acid,the methyl ester product was prepared.

The methyl ester (1.79 g, 6.1 mmol) from Step A above, was dissolved indioxane/water (20 mL/15 mL) at room temperature. Lithium hydroxide(0.258 g, 6.2 mmol) was added to the solution. After a few hours morelithium hydroxide was added (0.128 g, 3.0 mmol) and the reaction wasstirred for another hour. After this time the reaction was concentratedand then taken up in water. The solution was extracted two times withether. The aqueous phase was then acidified and extracted three timeswith ethyl acetate. The organic fractions were then dried over sodiumsulfate, filtered and concentrated. Product was isolated by columnchromatography (95% EtOAc/Hex, 0.05% HOAc) to give the product (1.66 g,98%).

¹H NMR (300 MHz, CDCl₃) 1.49 (m, 2H), 1.68 (m, 1H), 1.82 (m, 2H), 2.44(m, 1H) 3.32 (m, 1H), 3.58 (m, 1H), 5.57 (m, 1H), 7.65 (m, 1H), 7.80 (m,1H), 8.32 (m, 2H), 10.04 (bs, 1Hppm).

The nitro compound was dissolved in an excess of methanol (20 mL) andcovered by a blanket of argon. 5% Palladium on carbon was added(catalytic) and a hydrogen balloon was attached to the flask. Theatmosphere of the system was purged under vacuum and replaced withhydrogen. This step was repeated for a total of three times. Thereaction was then stirred under hydrogen overnight. After this time theballoon was removed and the solution was filtered through celitefollowed by several rinses with methanol. The filtrate was concentratedand dried on the vacuum line to provide the desired aniline product(1.33 g, 90%).

¹H NMR (300 MHz, CDCl₃) 1.40 (m, 2H), 1.50 (m, 1H), 1.68 (m, 2H), 2.33(m, 1H) 3.18 (m, 1H), 3.62 (m, 1H), 5.39 (m, 1H), 6.12 (bs, 2H), 6.75(m, 2H), 7.12 (m, 1H)ppm. Mass Spectra, calculated: 248, found: 249.1(M+1)⁺

Preparative Examples 121-123

Following the procedure described in Preparative Example 120, but usingthe commercially available amine and benzoic acid indicated, theintermediate products in the table below were obtained.

1. Yield (%) Carboxylic 2. (M + 1)⁺ Prep Ex Acid Amine Product 3. Note121

1. 21 2. 251.0 122

1. 21 2. 265.0 3. Skipped step B 123

1. 15 2. 264.0 3. Skipped step B

Preparative Example 124

Step A

3-Nitrosalicylic acid (500 mg, 2.7 mmol), 1,3-dicyclohexylcarbodiimide(DCC) (563 mg) and ethyl acetate (10 mL) were combined and stirred for10 min. (R)-(−)-2-pyrrolidinemethanol (0.27 mL) was added and theresulting suspension was stirred at room temperature overnight. Thesolid was filtered off and the filtrate was either concentrated down anddirectly purified or washed with 1N NaOH. The aqueous phase wasacidified and extracted with EtOAc. The resulting organic phase wasdried over anhydrous MgSO₄, filtered and concentrated in vacuo.Purification of the residue by preparative plate chromatography (silicagel, 5% MeOH/CH₂Cl₂ saturated with AcOH) gave the desired compound (338mg, 46%, MH⁺=267).

Step B

The product from Step A above was stirred with 10% Pd/C under a hydrogengas atmosphere overnight. The reaction mixture was filtered throughcelite, the filtrate concentrated in vacuo, and the resulting residuepurified by column chromatography (silica gel, 4% MeOH/CH₂Cl₂ saturatedwith NH₄OH) to give the product (129 mg, 43%, MH+=237).

Preparative Examples 125-145

Following the procedure described for Preparative Example 124, but usingthe commercially available amine or the amine from the PreparativeExample indicated and 3-nitrosalicylic acid, the products in the tablebelow were obtained.

1. Yield (%) Prep Ex Amine Comm. Avail./From Prep. Ex. Product 2. (M +1)⁺ 125

1. 37 2. 298.1 126

1. 31 2. 310.1 127

1. 68 2. 294.1 128

1. 54 2. 365.9 129

1. 45 2. 316.1 130 110

1. 59 2. 293.1 131 111

1. 32 2. 362.0 132 114

1. 36 2. 342.0 133 112

1. 65 2. 300.0 134

1. 48 2. 321.1 135

1. 50 2. 300.1 136

1. 56 2. 299.2 137 115

1. 79 2. 280.1 138 116

1. 64 2. 307.1 139

1. 73 2. 304.2 140

1. 34 2. 264.0 141 117

1. 40 2. 307.1 142 113

1. 91 2. 307.1 143 118

1. 9.0 2. 326.0 144 119

1. 42 2. 329.0 145

1. 6.5 2. 236.1

Preparative Example 146

Step A

To a solution of tosylaziridine (J. Am. Chem. Soc. 1998, 120, 6844-6845,the disclosure of which is incorporated herein by reference thereto)(0.5 g, 2.1 mmol) and Cu(acac)₂ (55 mg, 0.21 mmol) in THF (5 mL) at 0°C. was added PhMgBr (3.5 ml, 3.0 M in THF) diluted with THF (8 mL)dropwise over 20 min. The resulting solution was allowed to graduallywarm to rt and was stirred for 12 h. Sat. aq. NH₄Cl (5 mL), was addedand the mixture was extracted with Et₂O (3×15 mL). The organic layerswere combined, washed with brine (1×10 mL), dried (MgSO₄) andconcentrated under reduced pressure. The crude residue was purified bypreparative TLC eluting with hexane/EtOAc (4:1) to afford 0.57 g (86%yield) of a solid. The purified tosylamine was taken on directly to thenext step.

Step B

To a solution of tosylamine (0.55 g, 1.75 mmol) in NH₃ (20 mL) at −78°C. was added sodium (0.40 g, 17.4 mmol). The resulting solution wasstirred at −78° C. for 2 h whereupon the mixture was treated with solidNH₄Cl and allowed to warm to rt. Once the NH₃ had boiled off, themixture was partitioned between water (10 mL) and CH₂Cl₂ (10 mL). Thelayers were separated and the aqueous layer was extracted with CH₂Cl₂(2×10 mL). The organic layers were combined,), dried (NaSO₄), andconcentrated under reduced pressure to a volume of ˜20 mL. 4N HCl indioxane (5 mL) was added and the mixture was stirred for 5 min. Themixture was concentrated under reduced pressure and the resultant cruderesidue was recrystallized from EtOH/Et₂O to afford 0.30 g (87% yield)of a solid.

Preparative Examples 147-156.10

Following the procedure set forth in Preparative Example 146 but usingthe requisite tosylaziridines and Grignard reagents listed in the Tablebelow, the following racemic amine hydrochloride products were obtained.

Prep Ex. Tosyl aziridine Grignard Reagent Amine hydrochloride Yield (%)147

MeMgBr

1. 19% 148

EtMgBr

1. 56% 149

n-PrMgBr

1. 70% 150

i-PrMgCl

1. 41% 151

BnMgCl

1. 61% 152

MeMgBr

1. 61% 153

EtMgBr

1. 66% 154

n-PrMgBr

1. 80% 155

i-PrMgBr

1. 27% 156

BnMgCl

1. 79% 156.1

52 156.2

49 156.3

61 156.4

57 156.5

64 156.6

64 156.7

45 156.8

23 156.9

40 156.10

15

Preparative Example 156.11

Step A

To a solution of the amine (118 mg) from Preparative Example 148 inCH₂Cl₂ (10 ml) was added triethylamine (120 ul), R-Mandelic Acid (164mg), DCC (213 mg) and DMAP (8.8 mg)and let stir for 40 hr. The mixturewas diluted with CH₂Cl₂ and washed with saturated ammonium chloride,dried over Na₂SO₄, filtered, and concentrated in vacuo. The crudematerial was purified by preparative plate chromatography (Hex/EtOAc4:1) to afford both isomers (A, 86 mg, 45%) (B, 90 mg, 48%).

Step B

To isomer B (90 mg) from above in dioxane (5 ml) was added 6M H₂SO₄ (5ml). The reaction was heated to 80° C. over the weekend. 2M NaOH addedto basify the reaction and extracted with ether. Ether layer washed withbrine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Theresidue was stirred in 4N HCl in dioxane for 30 min, concentrated invacuo and recrystallized in EtOH/ether to afford 55 mg of product (98%).

Step C

Isomer A (86 mg) was reacted following the procedure set forth in Step Babove to give the amine salt.

Preparative Example 156.12

The above nitro compound was reduced following the Preparative Example2, Step B.

Preparative Example 156.13

To a solution of 1,2-phenylenediame (1.5 g) in CH₂Cl₂ (30 ml) at 0° C.was added TEA (2.91 ml), followed by dropwise addition of MeSO₂Cl (1.07ml). The mixture was allowed to warm to room temperature and stirovernight. 1M HCl added and the layers were separated. The aqueous layerwas adjusted to pH=11 with solid NaOH, extracted with CH₂Cl₂. Thebasified aqueous layer was then neutralized using 3N HCl and extractedwith CH₂Cl₂, dried with Na₂SO₄, filtered, and concentrated in vacuo togive 1.8 g of product (71%).

Preparative Example 156.14

The above compound was prepared using the procedure set forth inPreparative Example 156.13, but using PhSO₂Cl.

Preparative Example 156.15

The nitro compound was reduced following a similar procedure as inPreparative Example 2, Step B.

Preparative Example 156.16

Step A

The known acid (410 mg) above (J. Med. Chem. 1996, 34,4654, thedisclosure of which is incorporated herein by reference thereto.) wasreacted following the procedure set forth in Preparative Example 2, StepA to yield 380 mg of an oil (80%).

Step B

The amide (200 mg) from above was reacted following the procedure setforth in Preparative Example 2, Step B to yield 170 mg of an oil (100%).

Preparative Example 156.17

Step A

To a solution of ketone (500 mg) in EtOH/water (3:1, 4 ml) at roomtemperature was added hydroxylamine hydrochloride (214 mg) followed byNaOH to afford a heterogenous mixture. The reaction was not complete soanother equivalent of hydroxylamine hydrochloride was added and refluxedovernight. The reaction was cooled to 0° C. and treated with 3N HCl andextracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo to give 500 mg of product (92%).

Step B

To a solution of oxime (300 mg) in THF (5 ml) at 0° C. was added LiAlH₄(266 mg) portionwise. The heterogenous solution was stirred at roomtemperature for 14 hr and then refluxed for 8 hr. The solution wascooled to 0° C. and water, 2M NaOH, water and ether were added to thereaction. The mixture was filtered through a celite pad. The filtratewas treated with 3N HCl. The aqueous layer was cooled to 0° C., basifiedwith NaOH pellets and extracted with ether. The ether layer was driedover MgSO₄, filtered, and concentrated in vacuo to afford the product(143 mg, 69%).

Preparative Example 156.18

Step A

Methoxyacetic acid (14 mL) in CH₂Cl₂ (120 mL) and cooled in an ice-waterbath was treated with DMF (0.9 mL) and oxalyl chloride (21 mL). Afterstirring at RT overnight, the mixture was concentrated in vacuo andredissolved in CH₂Cl₂ (120 mL). N-methyl-N-methoxylamine (20 g) wasadded and the mixture stirred at RT overnight. Filtration andconcentration in vacuo afforded the desired amide (21 g, 89%).

Step B

To a solution of the above amide (260 mg) in THF (5 ml) at −78° C. wasadded a solution of 2-thienyllithium (1M in THF, 2.15 ml). The solutionwas stirred for 2 hr at −78° C. and warmed to −20° C. for an additional2 hr. The reaction was quenched with saturated ammonium chloride andextracted with CH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered,and concentrated in vacuo to give 250 mg of product (82%).

Step C

The ketone from above (250 mg) was reacted via the procedure set forthin Preparative Example 156.17 Steps A and B to yield 176 mg of the amine(79%).

Preparative Example 156.19

Step A

To a solution of 3-chlorothiophene (1.16 ml) in ether (20 ml) at −10° C.was added n-BuLi (2.5M in hexane, 5 ml). After solution was stirred at−10° C. for 20 min, propionaldehyde (0.82 ml) in ether (20 ml) was addeddropwise and let warm to room temperature slowly. The reaction wasquenched with saturated ammonium chloride and extracted with CH₂Cl₂,washed with brine, dried over Na₂SO₄, filtered, and concentrated invacuo to give 1.37 g of product (62%).

Step B

The alcohol from Step A above was reacted via the procedures set forthin Preparative Example 75.75, Steps B and C to give the amine.

Preparative Example 156.20

Step A

To a solution of magnesium metal (360 mg) in THF (15 ml) at 0° C. wasadded 2-bromothiophene (1.45 ml) in THF (10 ml) dropwise over 20 min.The solution was warmed to room temperature for 3 hr, recooled to 0° C.whereupon a solution of cyclopropylacetonitrile (1 g) in ether (30 ml)was added dropwise via a syringe and let warm to room temperature andstir overnight. 3M HCl was added and washed with CH₂Cl₂. The aqueouslayer was basified with NaOH pellets and extracted with ether, driedwith Na₂SO₄, filtered, and concentrated in vacuo to give 625 mg ofproduct (68%).

Step B

The ketone was reacted via the procedure set forth in PreparativeExample 156.17 Step A to give the oxime.

Step C

The oxime from above was reacted via the procedure set forth inPreparative Example 156.17 Step B to give the amine.

Preparative Example 156.21

Step A

To a solution of CH₃ONHCH₃.HCl (780 mg) and acid chloride (1 g) inCH₂Cl₂ at 0° C. was added dry pyridine (1.35 ml) to afford aheterogenous mixture The solution was warmed to room temperature andstirred overnight. 1M HCl was added to the reaction and the organiclayer was separated, washed with brine, dried with Na₂SO₄, filtered, andconcentrated in vacuo to give 1 g of product (85%).

Step B

To a solution of EtI (614 ul) in ether (5 ml) at −78° C. was addedt-BuLi (1.7M in pentane, 9 ml) dropwise. The mixture was warmed to roomtemperature for 1 hr, cooled to −78° C. where the amide (1 g) from StepA in THF (4 ml) was added and allowed to warm to 0° C. for 2 hr. 1M HClwas added to the reaction and extracted with CH₂Cl₂, washed with brine,dried with Na₂SO₄, filtered, and concentrated in vacuo to give 500 mg ofproduct (63%).

Step C

To a solution of ketone (800 mg) in THF/water (10:1, 20 ml) at 0° C. wasadded sodium borohydride (363 mg) portionwise. The solution was stirredfor 2 hr at 0° C. The mixture was concentrated in vacuo, the residue wasdissolved in CH₂Cl₂, washed with 1N NaOH and brine, dried with Na₂SO₄,filtered, and concentrated in vacuo to give 560 mg of product (69%).

Step D

The alcohol from above was reacted via the procedures set forth inPreparative Example 75.75, Steps B and C to give the amine (176 mg,59%).

Preparative Example 156.22

Step A

Cyclopropylacetonitrile (12 mmol) in Et₂O (50 mL) at 0° C. was treatedwith PhMgBr (14 mmol) and the mixture was stirred for 2 hrs at 0° C.,then at RT overnight. Hydrochloric acid (3 M) was added, and afterstirring for an additional 12 hrs, the mixture was extracted withCH₂Cl₂, washed with brine, dried over Na₂SO₄, filtered and concentratedin vacuo to give the desired ketone (1.34 g, 70%).

Step B

Following the procedures set forth in Preparative Example 156.20 Steps Band C, the amine was prepared.

Preparative Example 156.23

The above amine was prepared using the procedures set forth in WO98/11064 (the disclosure of which is incorporated herein by referncethereto.

Preparative Example 157

Step A

By taking the known carboxylic acid (J. Med. Chem. 1996, 39, 4654-4666,the disclosure of wnich is incorporated herein by refernce thereto) andsubjecting it to the conditions outlined in Preparative Example 112, theproduct can be prepared.

Step B

Following a similar procedure used in Preparative Example 2, Step A,except using dimethylamine and the compound from Step A above, theproduct can be prepared.

Step C

Following a similar procedure used in Preparative Example 2, Step B,except using the compound from Step B above, the product can beprepared.

Preparative Example 158

Following a similar procedure used in Preparative Example 157, StepsA-C, except using trifluoromethylsulfonylchloride in Step A above, theproduct can be prepared.

Preparative Example 200

A solution of the known (J. Org. Chem, V 48, No: 6, 1983, P 763-767)isothiazole dioxide intermediate (50 mg, 0.19 mmol) and the phenolicamine from Preparative Example 3 (31 mg, 0.19 mmol) in a mixture ofacetone and dichloromethane (2 mL, 1:1) was stirred at room temperaturefor several hours. Solvents were removed under reduced pressure; theresidue was treated with acetone, precipitated product 3 was separated(20 mg, 27%).

Preparative Example 201

A solution of the known (J. Org. Chem, V 48, No: 6, 1983, P 763-767)isothiazole dioxide intermediate (53 mg, 0.2 mmol) and thecommercially-available amine (28 μL, 0.2 mmol) in acetone (2 mL) wasstirred at room temperature overnight. Concentration in vacuo affordedthe desired intermediate which was used directly.

Preparative Examples 300-365

If one were to follow a procedure similar to that set forth inPreparative Example 200, but using the amines and the isothiazoledioxideintermediates from the Preparative Examples indicated in the Tablebelow, the isothiazoledioxide intermediates could be obtained.

Prep Ex of Prep Iso- Prep. Ex of thiazole- Ex. Amine dioxide Product 3003 22

301 1001 22

302 19 22

303 13.32A 22

304 1316 22

305 13.32A 22

307 75.9 22

308 75.44 22

309 75.1 22

310 75.61 22

311 1048 22

312 75.20 22

350 3 22.2

351 1001 22.2

352 19 22.2

353 75.1 22.2

354 3 22.3

355 1001 22.3

356 19 22.3

357 75.1 22.3

358 3 22.4

359 1001 22.4

360 19 22.4

361 75.1 22.4

362 3 22.1

363 1001 22.1

364 19 22.1

365 75.1 22.1

Preparative Example 500.1

Step A

By using the nitro-amide from Preparative Example 13.3, Step A, theamidine structure can be prepared following a similar procedure to thatin Tetrahedron Lett., 2000, 41 (11), 1677-1680 (the disclosure of whichis incorporated herein by refernce thereto).

Step B

By using the product from Step A and the procedure set forth inPreparative Example 2, Step B, one could obtain the desiredamine-amidine.

Alternate Preparative Example 500.2

Step A

By treating the nitro-amide from Preparative Example 13.3, Step B withPOCl₃ and subsequently MeNH₂, according to procedures known in the art,one would obtain the desired compound.

Step B

By treating the product from Step A according to the procedure set forthin Preparative Example 13.3, Step E, one could obtain the desiredcompound.

Step C

By using the product from Step B and the procedure set forth inPreparative Example 2 Step B, one would obtain the desired compound.

Preparative Example 500.3

Step A

By following a similar procedure as that described in Zh. Obshch. Khim.,27, 1957, 754, 757 (the disclosure of which is incorporated herein byreference thereto), but instead using 2,4-dichlorophenol anddimethylphosphinic chloride, one would obtain the desired compound.

Step B

By following a similar procedure as that described in J. Organomet.Chem.; 317, 1986, 11-22 (the disclosure of which is incorporated hereinby reference thereto), one would obtain the desired compound.

Step C

By following a similar procedure as that described in J. Amer. Chem.Soc., 77, 1955, 6221 (the disclosure of which is incorporated herein byreference thereto), one would obtain the desired compound.

Step D

By following a similar procedure as that described in J. Med. Chem., 27,1984, 654-659 (the disclosure of which is incorporated herein byreference thereto), one would obtain the desired compound.

Alternate Preparative Example 500.4

Step A

By following a similar procedure as that described in Phosphorous,Sulfur Silicon Relat. Elem.; EN; 61, 12, 1991, 119-129 (the disclosureof which is incorporated herein by reference thereto), but instead using4-chlorophenol, one would obtain the desired compound.

Step B

By using a similar procedure as that in Phosphorous, Sulfur SiliconRelat. Elem.; EN; 61, 12, 1991, 119-129 (the disclosure of which isincorporated herein by reference thereto), but instead using MeMgBr, thedesired compound could be prepared.

Step C

By following a similar procedure as that described in J. Amer. Chem.Soc., 77, 1955, 6221 (the disclosure of which is incorporated herein byreference thereto), one would obtain the desired compound.

Step D

By following a similar procedure as that described in J. Med. Chem., 27,1984, 654-659 (the disclosure of which is incorporated herein byreference thereto), one would obtain the desired compound.

Preparative Example 500.5

By following a similar procedure as that set forth in J. Org. Chem.1998, 63, 2824-2828 (the disclosure of which is incorporated herein byreference thereto), but using CH₃CCMgBr, one could obtain the desiredcompound.

Preparative Example 500.6

Step A

By following the procedure set forth in Preparative Example 13.1, Step Busing 3-methoxythiophene, one could obtain the desired product.

Step B

By using the product from step A and following the procedure set forthin Preparative Example 13.19, Step E, the desired compound could beobtained.

Step C

By using the product from Step B and following the procedure set forthin Preparative Example 13.29, Step D, one could obtain the desiredcompound.

Step D

By using the product from Step C and following the procedure set forthin Preparative Example 13.3, Step B, the desired compound could beobtained.

Step E

By treating the product from Step D with n-BuLi at −78° C. in THF andquenching the resulting anion with CO₂ according to standard literatureprocedure, one could obtain the desired compound following aqueous acidwork up.

Step F

By using the product from Step E and the procedure set forth inPrepartive Example 13.19, Step C, one could obtain the desired compound.

Step G

By using the product from step F and following the procedure set forthin Preparative Example 13.19, Step E, the desired compound could beobtained.

Step H

By using the product from Step G and following the procedure set forthin Preparative Example 2, Step B, the desired compound could beobtained.

Preparative Example 500.7

Step A

If one were to use a similar procedure to that used in PreparativeExample 13.3 Step B, except using the hydroxy acid from Bioorg. Med.Chem. Lett. 6(9), 1996, 1043 (the disclosure of which is incorporatedherein by reference thereto), one would obtain the desired methoxycompound.

Step B

If one were to use a similar procedure to that used in PreparativeExample 13.19 Step B, except using the product from Step A above, onewould obtain the desired compound.

Step C

If one were to use a similar procedure to that used in Synth. Commun.1980, 10, p. 107 (the disclosure of which is incorporated herein byreference thereto), except using the product from Step B above andt-butanol, one would obtain the desired compound.

Step D

If one were to use a similar procedure to that used in Synthesis, 1986,1031 (the disclosure of which is incorporated herein by referencethereto), except using the product from Step C above, one would obtainthe desired sulfonamide compound.

Step E

If one were to use a similar procedure to that used in PreparativeExample 13.19 Step E, except using the product from Step D above, onewould obtain the desired compound.

Preparative Example 500.8

Step A

If one were to treat the product from Step C of Example 1125 with BuLi(2.2 eq.) in THF followed by quenching of the reaction mixture withN,N,-dimethylsulfamoyl chloride (1.1 eq.) then one would obtain

Step B

If one were to use the product of Step A above and follow Step E ofPreparative Example 500.7, then one would obtain the title compound.

Preparative Example 500.9

Step A

To a solution of 3-methoxythiophene (3 g) in dichloromethane (175 mL) at−78° C. was added chlorosulfonic acid (8.5 mL) dropwise. The mixture wasstirred for 15 min at −78° C. and 1.5 h at room temp. Afterwards, themixture was poured carefully into crushed ice, and extracted withdichloromethane. The extracts were washed with brine, dried overmagnesium sulfate, filtered through a 1-in silica gel pad. The filtratewas concentrated in vacuo to give the desired compound (4.2 g).

Step B

The product from Step A above (4.5 g) was dissolved in dichloromethane(140 mL) and added with triethylamine (8.8 mL) followed by diethyl aminein THF (2M, 21 mL). The resulting mixture was stirred at roomtemperature overnight. The mixture was washed with brine and saturatedsulfated (aq) and brine again, dried over sodium sulfate, filteredthrough a 1-in silica gel pad. The filtrate was concentrated in vacuo togive the desired compound (4.4 g).

Step C

The product from Step B above (4.3 g) was dissolved in dichloromethane(125 mL) and cooled in a −78° C. bath. A solution of boron tribromide(1.0 M in dichloromethane, 24.3 mL) was added. The mixture was stirredfor 4 h while the temperature was increased slowly from −78° C. to 10°C. H₂O was added, the two layers were separated, and the aqueous layerwas extracted with dichloro-methane. The combined organic layer andextracts were wahed with brine, dried over magnesium sulfate, filtered,and concentrated in vacuo to give 3.96 g of the desiredhydroxy-compound.

Step D

The product from step C above (3.96 g) was dissolved in 125 mL ofdichloromethane, and added with potassium carbonate (6.6 g) followed bybromine (2 mL). The mixture was stirred for 5 h at room temperature,quenched with 100 mL of H₂O. The aqueous mixture was addjusted to pH˜5using a 0.5N hydrogen chloride aqueous solution, and extracted withdichloromethane. The extracts were washed with brine, dried over sodiumsulfate, and filtered through a celite pad. The filtrate wasconcentrated in vacuo to afford 4.2 g of the desired bromo-compound.

Step E

The product from Step D (4.2 g) was dissolved in 100 mL of acetone andadded with potassium carbonate (10 g) followed by iodomethane (9 mL).The mixture was heated to reflux and continued for 3.5 h. After cooledto room temperature, the mixture was filtered through a Celite pad. Thefiltrate was concentrated in vacuo to a dark brown residue, which waspurified by flash column chromatography eluting withdichloromethane-hexanes (1:1, v/v) to give 2.7 g of the desired product.

Step F

The product from step E (2.7 g) was converted to the desired iminecompound (3 g), following the similar procedure to that of PreparativeExample 13.19 step D.

Step G

The imine product from step F (3 g) was dissolved in 80 mL ofdichloromethane and cooled in a −78° C. bath. A solution of borontribromide (1.0 M in dichloromethane, 9.2 mL) was added dropwise. Themixture was stirred for 4.25 h from −78° C. to 5° C. H₂O (50 mL) wasadded, and the layers were separated. The aqueous layer was extractedwith dichloromethane. The organic layer and extracts were combined,washed with brine, and concentrated to an oily residue. The residue wasdissolved in 80 mL of methanol, stirred with sodium acetate (1.5 g) andhydroxyamine hydrochloride (0.95 g) at room temperature for 2 h. Themixture was poured into an aqueous mixture of sodium hydroxide (1.0 Maq, 50 mL) and ether (100 mL). The two layers were separated. Theaqueous layer was washed with ether three times. The combined etherwashings were re-extracted with H₂O once. The aqueous layers werecombined, washed once with dichloromethane, adjusted to pH ˜6 using 3.0M and 0.5 M hydrogen chloride aqueous solutions, and extracted withdichloromethane. The organic extracts were combined, washed with brine,dried over sodium sulfate, and concentrated in vacuo to give 1.2 g ofdesired amine compound.

Preparative Example 600

Step A

Following the procedure set forth in Preparative Example 13.19 Step D,the imine was prepared from the known bromoester (1.0 g) to yield 1.1 g(79%) as a yellow solid.

Step B

The product of Step A (0.6 g) was reacted following the procedure setforth in Preparative Example 13.19 Step E to give the amine product 0.19g (64%).

Step C

The product of Step B (1.0 g) was reacted following the procedure setforth in Preparative Example 13.19 Step B to give the acid as yellowsolid 0.9 g (94%).

Step D

The product of Step C (0.35 g) was reacted following the procedure setforth in Preparative Example 13.19 Step E to give the amino acid asyellow solid 0.167 g (93%).

Preparative Example 601

Step A

To a solution of 2-methyl furan (1.72 g) in ether was added BuLi (8.38mL) at −78° C. and stirred at room temperature for half an hour. Thereaction mixture again cooled to −78° C. and quenched with cyclopropylamide 1 and stirred for two hours at −78° C. and slowly warmed to roomtemperature. The reaction mixture stirred for three hours at roomtemperature and quenched with the addition of saturated ammoniumchloride solution. The mixture was taken to a separatory funnel, washedwith water, brine and dried over anhydrous sodium sulfate. Filtrationand removal of solvent afforded the crude ketone, which was purified byusing column chromatography to afford the ketone 3.0 g (87%) as a paleyellow oil.

Step B

To a solution of ketone (1.0 g) from Step A above in THF (5.0 mL) at 0°C. was added R-methyl oxazoborolidine (1.2 MI, 1M in toluene) dropwisefollowed by addition of a solution of borane complexed with dimethylsulfide (1.85 mL, 2M in THF). The reaction mixture was stirred for 30minutes at 0° C. and than at room temperature for one hour. The reactionmixture was cooled to 0° C. and MeOH was added carefully. The mixturewas stirred for 20 minutes and was concentrated under reduced pressure.The residue was extracted with ether, washed with water, 1M HCl (10 mL),saturated sodium bicarbonate (10.0 mL) water and brine. The organiclayer was dried over anhydrous sodium sulfate, filtered and removal ofsolvent afforded the crude alcohol which was purified by silica gelchromatography to afford the pure alcohol 0.91 g (91%) as yellow oil.

Preparative Example 601.A

Step A

If one were to follow the procedure set forth in Preparative Example601, but using the cyclopentylamide instead of the cyclopropylamide(prepared according to standard procedures), then one would obtain thedesired alcohol.

Step B

If one were to follow the procedure set forth in Preparative Example13.25, but instead using the alcohol from Step A above, then one wouldobtain the title amine.

Preparative Example 601.B

Step A

If one were to follow the procedure set forth in Preparative Example601.A, but using 4-isopropylfuran instead of 5-methylfuran, then onewould obtain the desired alcohol.

Step B

If one were to follow the procedure set forth in Preparative Example13.25, but instead using the alcohol from Step A above, then one wouldobtain the title amine.

Preparative Example 602

Step A

An equimolar mixture of 2-methylfuran (1.0 g) and anhydride (2.6 g) wasmixed with SnCl₄ (0.05 mL) and heated at 100° C. for 3 hours. Aftercooling the reaction mixture, water (10 mL) was added, followed bysaturated sodium carbonate solution until it becomes alkaline. Thereaction mixture was extracted with ether several times and the combinedether layer was washed with water, brine and dried over anhydrous sodiumsulfate. Filtration and removal of solvent afforded the crude ketone,which was purified by using silica gel chromatography to afford theketone 0.9 g (43%) as a yellow oil.

Step B

The title alcohol was obtained following a similar procedure set forthin the Preparative Example 601.

Preparative Example 603

To a solution of 5-methyl furan-2-aldehyde (1.0 g) and3-bromo-3,3-difluoropropene (2.24 g) in DMF (30 mL) was added indiumpowder (1.66 g) and lithium iodide (50.0 mg). The reaction mixture wasstirred over night, diluted with water and extracted with ether. Theether layer was washed with water, brine and purified by silica gelchromatography to afford the pure alcohol 2.8 g (92%).

Preparative Examples 603A-603F

If one were to follow the procedure of Preparative Example 64, using thealdehydes, amino alcohols and organolithiums in the Table below, thenthe optically pure amine Products in the Table below would be obtained.

Prep. Ex. Aldehyde Amino Alcohol Organolithium Product 603A

iPrLi

603B

tBuLi

603C

tBuLi

603D

tBuLi

603E

iPrLi

603F

iPrLi

Preparative Examples 604-611

Following a similar procedure set forth in Preparative Examples 13.25 or601 the following Alcohols were prepared.

Prep Ex Furan Electrophile Alcohol Yield 604

86% 605

69% 606

84% 607

82% 608

60% 609

65% 610

82% 611

89%

Preparative Examples 620-631

Following a similar procedure to that set forth in Preparative Example13.25 the following Amines were prepared from the correspondingAlcohols.

Prep Ex ALCOHOL AMINE % YIELD 620

28 621

58 622

69 623

81 624

82 625

45 626

57 627

58 628

54 629

53 630

50 631

  82%

Preparative Example 1001

Step A

Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to a mixture of2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol) (preparedaccording to known method, see: EP0897904B1), N,N-dimethylformamide (0.3mL), and dichloromethane (40 mL) with stirring at rt. The reactionmixture was stirred overnight. Evaporation of solvent and excess oxalylchloride and drying under vacuum afforded2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was usedwithout purification.

Step B

A solution of 2-methoxy-6-(trifluoromethyl)benzoyl chloride (ca. 6.81mmol) from Step A above in dichloromethane (20 mL) was added dropwise toa mixture of 4-(dimethylamino)pyridine (42 mg, 0.34 mmol), triethylamine(2.8 mL, 20.09 mmol), and 2 M dimethylamine solution in tetrahydrofuran(7 mL,14 mmol), and dichloromethane (30 mL) with stirring at rt. Thereaction mixture was stirred overnight. A mixture of dichloromethane andwater was added. The organic phase was separated, washed with 1N HClsolution, water, and saturated sodium bicarbonate solution andconcentrated. The residue was purified by column chromatography (ethylacetate:hexanes, 3:1 v/v) to give the product as a white solid (1.24 g,74% over two steps).

Step C

A mixture of the amide from Step B above (1.8 g, 7.28 mmol), carbontetrachloride (25 mL), and iron powder (305 mg, 5.46 mmol) was cooled to0° C. Bromine (0.94 mL, 18.34 mmol) was added dropwise with stirring.After addition, the mixture was stirred at rt for 1 h and at 50° C. for3 h. The mixture was cooled to rt, diluted with dichloromethane, andslowly poured to a cold 10% NaHSO₃ solution. After stirring at rt for0.5 h, the organic layer was separated and concentrated to give theproduct as a white solid (2.26 g, 95%).

Step D

Concentrated sulfuric acid (10 mL) was added dropwise to a flask chargedwith the bromide from Step C above (600 mg, 1.84 mmol) at 0° C. withstirring. A mixture of nitric acid (0.2 mL, 4.76 mmol) and concentratedsulfuric acid (0.3 mL) was then added dropwise. After addition, themixture was stirred at rt for 3 h. The mixture was added to ice-water,neutralized with 15% NaOH solution to pH 7, and extracted withdichloromethane. The organic layer was concentrated to give the productas a white solid (621 mg, 91%). mp 92° C., m/e 371 (MH⁺).

Step E

A solution of the compound from Step D above (1.2 g, 3.23 mmol) indichloromethane (50 mL) was cooled to −75° C. 1 M BBr₃ solution indichloromethane (7.5 mL, 7.5 mmol) was added dropwise with stirring. Themixture was stirred at −75° C. for 2 h. The mixture was added toice-water. After stirring at rt for 0.5 h, the mixture was extractedwith dichloromethane. The organic was concentrated and the residue waspurified by column chromatography (dichloromethane-methanol, 9:1 v/v) togive the product as a yellow solid (1.05 g, 91%). m/e 357 (MH⁺).

Step F

A mixture of the compound from Step E above (1.08 g, 3.02 mmol),methanol (30 mL), and 10% Pd-C (250 mg),was subjected to hydrogenationat 50 psi at rt for 6 h. The mixture was filtered through a layer ofCelite. The filtrate was concentrated to give the title compound as apale yellow solid (930 mg, 96%). mp 132° C., m/e 249.

Preparative Example 1002

Step A

To a cooled (−70° C.) etherial (45 mL dry) solution of 3-bromothiophene(3.8 mL) was added BuLi (30 mL of 1.6M in hexane) dropwise, and themixture was stirred at −70° C. for 20 min. Acetophenone (4.6 mL) inether (6 mL) was added dropwise with stirring at −70° C. After 3 hrs,the mixture was warmed to RT and sat. NH₄Cl (aq) was added and themixture was extracted with ether. The organic phase was dried (Na₂SO₄)and concentrated in vacuo to give the title compound which was used inStep B without further purification.

Step B

The crude product from Step A above was stirred with oxalic acid (0.375g) at 70° C. under reduced pressure for 3 hr, then cooled to RT andextracted with ether. The organic phase was dried (Na₂SO₄) andconcentrated in vacuo to give the product as a pale yellow liquid (5.7g, 78% for Steps A-B).

Step C

To the product from Step B above (4.2 g) diluted with dichloromethane(30 mL) and containing triethylsilane (6 mL) was added TFA (3 mL) indichloromethane (7.5 mL). After stirring at RT for 10 min, the mixturewas concentrated in vacuo to give the product as a colorless liquid(4.61 g, 80%).

Step D

To an etherial (3.5 mL dry) solution of the thiophene product (1.5 g)from Step C above was added BuLi (3.2 mL of 2.5M), and the mixture washeated at reflux for 15 min, cooled to RT, and DMF (0.8 mL) in ether(3.5 mL) was added dropwise. After stirring for 30 min, sat. NH₄Cl (aq)was added and the mixture was extracted with ether. The organic phasewas dried (Na₂SO₄) and concentrated in vacuo to give the title compound(1.71 g, 98%).

Preparative Example 1002B

Step A

Following the procedure described in Preparative Example 1002, Step A,but using acetone instead of acetophenone, 2-thiophen-3-yl-2-propanolwould be obtained.

Step B, C, D

Following the procedures described in Preparative Example 1002, steps Bto D, the product from step A above would be converted to the titled4-isopropyl-2-thiophen-aldehyde.

Preparative Example 1003

Step A

The aldehyde (0.50 g) was combined with ethylene glycol (1 mL), benzene(40 mL) and PTSA monohydrate (30 mg) and stirred at reflux for 20 hr.Cool to room temperature, add EtOAc and sat. NaHCO₃ (aq) solution,separate the organic phase, concentrate in vacuo, and purify by silicagel chromatography (EtOAc-Hex, 1:4) to give a colorless liquid (60 mg)

Step B

The product from Step A above (0.607 g) was stirred at 45° C. overnightwith 1N NaOH (aq), then cooled to room temperature, acidified with 3NHCl and extracted with EtOAc. Washing with brine and concentration invacuo gave a solid (5.0 g).

Step C

Following a similar procedure as that used in Preparative Example 1,except using the product from Step B above and dimethylamine in THF(2M), the product was obtained (1.21 g crude).

Step D

The product from Step C above was dissolved in THF and stirred with 0.3NHCl (aq) and stirred at RT for 4 hr. Concentration in vacuo gave a paleyellow oil (1.1 g, 67%).

Preparative Example 1004

Step A

To a cooled (−78° C.) solution of methoxybenzofuran-2-carboxylic acid (1g) was added DIBAL (30 mL, 1M in THF). After stirring for 20 min, themixture was warmed to RT and stirred for 4 hr, then poured into sat.NH₄Cl (aq) (35 mL). After stirring at RT for 20 min, 6M HCl (aq) wasadded and the mixture was extracted with EtOAc, the organic phase driedand then concentrated in vacuo. Purification by silica gelchromatography (EtOAc-hexane, 3:7) afforded the alcohol as a solid (0.4g, 97%).

Step B

A mixture of the product from Step A above (0.9 g), EtOAc (50 mL) andMnO2 (5.2 g) was stirred at RT for 22 h, then filtered and concentratedin vacuo. The solid was redissolved in EtOAc (50 mL), MnO2 (5.2 g) wasadded and the mixture was stirred for 4 additional hrs. Filtration,concentration and silica gel purification (EtOAc-Hexane, 1:3) gave thetitle compound as a solid (0.60 g, 67%).

Preparative Example 1004A

Step A

To a stirred solution of potassium t-butoxide (2.5 g) in HMPA (20 ml)was added 2-nitropropane (2 ml) dropwise. After 5 min, a solution ofmethyl-5-nitro-2-furoate (3.2 g) in HMPA (8 ml) was added to the mixtureand stirred for 16 hr. Water was added and the aqueous mixture wasextracted with EtOAc. The EtOAc layer was washed with water, dried withMgSO₄, filtered and concentrated in vacuo. The crude material waspurified by flash column chromatography (Hex/EtOAc, 6:1) to yield 3.6 gof product (90%).

Step B

To a solution of product from Step. A (3.6 g) in toluene (16 ml) wasadded tributyltin hydride (5.4 ml) followed by AlBN (555 mg). Themixture was heated to 85° C. for 3.5 hr. After cooling, the mixture wasseparated by flash column chromatography (Hex/EtOAc, 7:1) to afford 2.06g of product (73%).

Step C

To a solution of product from Step B (2.05 g) in THF (60 ml) at 0° C.was added a solution of LAH (1M in ether, 12.8 ml). The reaction wasstirred at room temperature for 30 min. Water and 1M NaOH was addeduntil a precipitate formed, diluted with EtOAc, stirred for 30 min andthen filtered through a celite pad. The organic filtrate wasconcentrated in vacuo to give 1.56 g of product (93%).

Step D

To a solution of product from Step C (2.15 g) in CH₂Cl₂ (100 ml) wasadded Dess-Martin oxidant (7.26 g) in CH₂Cl₂ (45 ml) and stirred for 30min. The mixture was diluted with ether (200 ml). The organic layer waswashed with 1N NaOH, water and brine, dried with MgSO₄, filtered andconcentrated in vacuo to give oil and solid. The material was extractedwith ether and filtered. Some solid crystallized out from the filtrate,filtered again, and the filtrate was concentrated in vacuo to give 2.19g of product.

Preparative Example 1004B

Step A

To a suspension of 5-bromo-2-furoic acid (15 g) in CH₂Cl₂ (275 ml) atroom temperature was added oxalyl chloride (6.9 ml) followed by acatalytic amount of N,N′-dimethylformamide ((0.3 ml). The mixture wasstirred for 1 hr, whereupon, EtOH (20 ml) and TEA (22 ml) were added andthen let stir overnight. The mixture was concentrated in vacuo andextracted with hexanes and hexanes/CH₂Cl₂. The extracts wereconcentrated in vacuo to give an oil (17.2 g, 93%).

Step B

The product from Step A (17.2 g), aluminum trichloride (19.52 g) andcarbon disulfide (150 ml) were combined in a flask. A solution ofn-octadecyl bromide (24.4 g) in carbondisulfide (50 ml) was addeddropwise over 45 min. The reaction was stirred for 2.5 hr, whereupon,300 ml of crushed ice and water were added. The layers were separatedand the organic layer was washed with saturated sodium bicarbonate,water, and brine. The organic layer was dried with Na₂SO₄ andconcentrated in vacuo. The crude material was purified by flash columnchromatography (hexanes/CH₂Cl₂, 3:1) to yield 7.91 g of product (37%).

Step C

To the product from step B (7.9 g) in THF (140 ml) at −10° C. was addeda solution of LAH (1M in THF, 28.5 ml). The solution was stirred for 2.5hrs at 15° C. Water and 1M NaOH were added carefully to the mixture,followed by EtOAc and let stir for 1.5 hr. The reaction was filteredthrough a silica pad and the filtrate was concentrated in vacuo to yield6.48 g of crude product (100%).

Step D

The product from Step C (6.32 g) was dissolved in THF (140 ml) andcooled to −78° C. A solution of t-BuLi (2.5M in hexanes, 22 ml) wasadded dropwise and let stir for 15 min. An excess of water (70 ml) wasthen added and let the reaction stir another hour. CH₂Cl₂ (300 ml) andbrine (50 ml) were added and the layers were separated. The organiclayer was dried with Na₂SO₄ and concentrated in vacuo to give 5.33 g ofcrude product.

Step E

To a solution of the product from Step D (5.33 g) in CH₂Cl₂ (100 ml) wasadded a solution of Dess-Martin periodinane in CH₂Cl₂ (15wt %, 12.6 g).The mixture was stirred for 1.5 hr and then diluted with ether (400 ml)and washed with 1N NaOH, water and brine. The organic layer was driedwith Na₂SO₄ and filtered through a magnesium sulfate/silica pad. Thefiltrate was concentrated in vacuo and purified via flash columnchromatography (hex/EtOAc, 50:1, 25:1) to yield 3.06 g of an oil (74%).

Preparative Example 1005

Following a similar procedure as that described in Preparative Example1004, except using 5-chlorobenzofuran-2-carboxylic acid (1.5 g), thetitle compound was obtained (solid, 0.31 g, 24%).

Preparative Example 1006

Step A

The sulfonyl chloride from Preparative Example 13.29 Step A (1.5 g) wasstirred with AlCl3 and benzene for 15 min at 20° C. Treatment with NaOH,extraction with Et₂O, concentration in vacuo, and purification by columnchromatography (silica, hexane-EtOAc, 5:2) gave the phenylsulfone (1.5g, 84%, MH⁺=255).

Step B

Following similar procedures as those used in Preparative Example 13.29Steps C-G, except using the sulfone from Step A above, the titlecompound was prepared (0.04 g, 27%, MH⁺=256).

Preparative Example 1030

Step A

The product of Preparative Example 34.18 Step B (2 g, 8 mmol) wasstirred with morpholine (0.9 mL, 10.29 mmol) and K₂CO₃ (2.2 g, 15.9mmol) in 50 mL of acetone at RT to obtain the morpholinobutylfuranderivative (1.22 g, 73%).

Step B

Following a similar procedure as that in Preparative Example 34.18 StepD, but using the product (1.2 g) from Step A above, the title aldehydewas prepared (0.9 g, 66%, 1:0.7 regioisomeric mixture).

Preparative Example 1030-A

Following a similar procedure as that in Preparative Example 1030 StepsA-B, but using N-methylpiperazine instead of morpholine, the titlealdehyde could be prepared.

Preparative Example 1030-B

Following a similar procedure as in Preparative Example 1030 Steps A-B,but using N,N-dimethylamine instead of morpholine, the title aldehydecould be prepared.

Preparative Example 1031

A solution of 5-bromobenzofuran (950 mg, 4.82 mmol) in anhydrous ether(12 mL) was cooled to −78° C. 1.7M tert-BuLi solution in pentane (6 ml,10.2 mmol) was added dropwise under argon. After addition, the mixturewas stirred at −78° C. for 20 min, followed by addition of a mixture ofDMF (0.8 mL) and ether (1 mL). The mixture was allowed to warm to rt andstirred for 0.5 h. Ethyl acetate was added. The mixture was poured tosaturated ammonium chloride solution. The organic layer was separatedand concentrated. The residue was purified by column chromatography(ethyl acetate-hexanes, 1:5 v/v) to give the title compound as a paleyellow solid (490 mg, 70%).

Preparative Examples 1040-1054

Following the procedure set forth in Preparative Example 64 but usingthe commercially available (or prepared) aldehyde, aminoalcohols, andorganolithium reagents in the Table below, the optically pure amineproducts in the Table below were obtained.

Prep. Amino Organo- 1. Yieid (%) Ex. Aldehyde Alcohol lithium Product 2.(M + 1)⁺ 1040

EtLi

1. 24% 2. 267 1041

EtLi

1. 94% 2. 176 (m/e) 1042

EtLi

1. 67% 2. 229 (M − 16) 1043

i-PrLi

1. 60% 2. 151 [M − 16] 1044

EtLi

1. 74% 2. 194 (M − 16) 1045

EtLi

1. 33% 2. 165 [M − NH2]⁺ 1046

EtLi

1. 31 2. 179 [M − NH2]⁺ 1047

t-BuLi

1. 31% 2. 188 1048

t-BuLi

1. 10% 2. 154 1049

EtLi

1. 73% 2. 137 [M − NH2]⁺ 1051

t-BuLi

1. 17% 1054

t-BuLi

1. 79% 2. 151 (M − 16)

Preparative Examples 1100-1126

Following the procedure set forth in Preparative Example 34 but usingthe commercially available aldehydes and Grignard/Organolithium reagentslisted in the Table below, the amine products were obtained.

Organo-metallic 1. Yield (%) Prep. Ex. Aldehyde Reagent Product 2. (M +1)⁺ 1100

t-BuLi

1. 83% 2. 190 (M − 16) 1101

t-BuLi

1. 46% 2. 204 1102

t-BuLi

1. 48% 2. 194 1103

t-BuLi

1. 51% 2. 194 1104

t-BuLi

1. 12% 2. 238 1105

t-BuLi

1. 39% 2. 234 1106

t-BuLi

1. 44% 2. 194 (m/e) 1107

t-BuLi

1. 57% 2. 150 (M − 16) 1108

t-BuLi

1. 31% 2. 224 1109

t-BuLi

1. 11% 2. 224 1110

t-BuLi

1. 57% 2. 224 1111

t-BuLi

1. 21% 2. 224 1112

c-Pentyl-Li

1. 58% 2. 190 1113

t-BuLi

1. 20% 2. 248 1114

t-BuLi

1. 24% 2. 232 1115

EtLi

1. 32% 2. 177 (M − NH2) 1116

t-BuLi

1. 26% 2. 205 (M − NH2) 1117

t-BuLi

1. 50% 2. 190 (M − NH2) 1118

t-BuLi

1. 29% 2. 200 1119

t-BuLi

1. 28% 2. 232 1120

t-BuLi

1. 76% 2. 224 1121

t-BuLi

1. 40% 2. 206 1122

t-BuLi

1. 38% 2. 236 1123

t-BuLi

1. 70% 2. 192 1124

t-BuLi

1. 81% 2. 204 1125

t-BuLi

33% 1126

t-BuLi

50%

Preparative Examples 1200A-1204A

Following the procedure set forth in Preparative Example 13.29 but usingthe commercially available amines, the hydroxyaminothiophene productslisted in the Table below were obtained.

Prep. 1. Yield (%) Ex. Amine Product 2. (M + 1)⁺ 1200A

1. 3% 2. 342 1201A

1. 41% 2. 265 1202A

1. 17% 2. 237 1203A

1. 1% 1204A

1. 15% 2. 375.1

Preparative Example 1205A

Step A

Dibenzylsulfonamide-thiophene-amine (660 mg, 1.76 mmol), available fromPreparative Example 1204A, was stirred with 4 mL of concentratedsulfuric acid at room temperature for 5 h. Ice water (50 mL) was added.The aqueous mixture was adjusted to pH ˜5 using a 1.0M NaOH aqueoussolution, and extracted with ethyl acetate (200 mL×4). The organicextracts were washed with H₂O and brine, dried over MgSO₄, filtered, andconcentrated in vacuo to yield 237 mg of the desired sulfonamide amine(69%, MH⁺=194.23, [M−NH₂]⁺=178).

Preparative Examples 1300

The title compound from Preparative Example 13.32 (0.35 g) was treatedwith concentrated sulfuric acid (3 mL) for 6 hrs, then poured on ice,and the pH adjusted to 4 with NaOH. Extraction with EtOAc, and drying ofthe organic phase over Na₂SO₄ gave the title compound (159 mg, 64%,MH⁺=223).

Preparative Examples 1301

Step A

Following the procedure set forth in Preparative Example 605 but usingthe commercially available fluoroisopropylester, the alcohol product wasobtained (1.2 g, 84%, M−OH=155).

Step B

Following the procedure set forth in Preparative Example 625 but usingthe alcohol from Step A above, the amine product was obtained (350 mg,35%, M−NH2=155).

Preparative Examples 1302

Step A

Following a similar procedure as that used in Preparative Example 13.29Step B, except using the commercially available arylsulfonylchloride(0.15 g) and diethylamine (2.2 eq), the dimethylsulfonamide was obtained(0.12 g, 71%, MH⁺=323).

Step B

Following a similar procedure as that used in Preparative Example 13.29Step C, except using the product from Step A above (0.12 g), the phenolwas obtained (0.112 g, 98%).

Step C

Following a similar. procedure as that used in Preparative Example 10.55Step C, except using the product from Step B above (0.112 g), the titlecompound was obtained (0.1 g, 99%, MH⁺=245).

Preparative Examples 1303

Following a similar procedure as that used in Preparative Example 1302Steps A-C, except using piperidine in Step A (0.078 g) instead ofdiethylamine, the title compound was obtained (0.070 g, 35%, MH⁺=257).

Preparative Examples 1304

Following a similar procedure as that used in Preparative Example 1302Steps A-C, except using dimethylamine (2M in THF) in Step A instead ofdiethylamine, the title compound was obtained (1.92 g, 72%, MH⁺=217).

Preparative Examples 1304A

Following a similar procedure as that used in Preparative Example 1302Steps A-C, except using morpholine in Step A instead of diethylamine,the title compound could be obtained.

Preparative Examples 1304B

Following a similar procedure as that used in Preparative Example 1302Steps A-C, except using N-methylamine in Step A instead of diethylamine,the title compound could be obtained.

Preparative Examples 1305

Step A

Following a similar procedure as that used in Preparative Example 1302Step A, except using the phenethylamine indicated (4.99 g), the productwas obtained (5.96 g, 86%, MH⁺=210).

Step B

The compound from Step A above (5.0 g) was added to 30 g of PPA at 150°C. and the resulting mixture stirred for 20 min, before being poured onice and extracted with dichloromethane. The organic phase was dried overMgSO4, concentrated in vacuo and purified by silica gel chromatography(EtOAc:MeOH, 95:5) to give the product (0.5 g, 9%).

Step C

Following a similar procedure as that used in Preparative Example 13.3Step D, except using the compound from Step B above (0.14 g), theproduct was obtained (0.18 g, 87%, MH⁺=256).

Step D

Following a similar procedure as that used in Preparative Example 11Step B, except using the compound from Step C above (0.18 g), theproduct was obtained (0.17 g).

Step E

Following a similar procedure as that used in Preparative Example 13.3Step B, except using the compound from Step D above (0.17 g), theproduct was obtained (0.17 g, 95%, MH⁺=315).

Step F

Following a similar procedure as that used in Preparative Example 13.29Step C, except using the product from Step E above (0.17 g), thenitrophenol was obtained (0.165 g, 99%, MH⁺=303).

Step G

Following a similar procedure as that used in Preparative Example 10.55Step C, except using the product from Step F above (0.165 g), the titlecompound was obtained (0.128 g, 86%, MH⁺=193).

Preparative Examples 1306

Step A

Following a similar procedure as that used in Preparative Example 11Step B, except using the lactam (0.179 g), the title compound wasobtained (0.25 g, 25%).

Step B

Following a similar procedure as that used in Preparative Example 13.29Step C, except using the product from Step A above (0.055 g), the phenolwas obtained (0.045 g, 99%).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, except using the product from Step B above (0.045 g), the titlecompound was obtained (0.022 g, 57%, MH⁺=179).

Preparative Examples 1307

Following a similar procedure as that used in Preparative Example 2,except using 3(R)-hydroxypyrrolidine HCl (1.36 g), the title compoundwas obtained (2.25 g, 89%).

Preparative Examples 1308

Following a similar procedure as that used in Preparative Example 2,except using morpholine, the title compound was obtained (3.79 g).

Preparative Examples 1309

Step A

Following a similar procedure as that used in Preparative Example 13.29Step B, except using the commercially availablenitrophenylsulfonylchloride and diethylamine (2.2 eq), thedimethylsulfonamide was obtained (90%, MH⁺=231).

Step B

Following a similar procedure as that used in Preparative Example 10.55Step C, except using the product from Step B above, the title compoundwas obtained (45%, MH⁺=201).

Preparative Examples 1310

Step A

Following a similar procedure as that used in Preparative Example 13.29Step B, except using the commercially available nitrobenzoylchloride andthe commercially available amine indicated, the benzamide was obtained(13%, MH⁺=253).

Step B

Following a similar procedure as that used in Preparative Example 10.55Step C, except using the product from Step B above, the title compoundwas obtained (94%, MH⁺=223).

Preparative Examples 1310A

Step A

Following a similar procedure as that used in Preparative Example 13.29Step B, except using the commercially available nitrobenzoylchloride anddimethylamine, the benzamide could be obtained.

Preparative Examples 1311

Step A

To a benzene (20 mL) solution of methoxythiophenesulfonylchloride (1.5g) was added AlCl₃ (2.0 g) at RT. After 15 min, the mixture was added to0.1N HCl (aq) with stirring, then extracted with Et₂O. Washing theorganic phase with bring, drying over MgSO₄, concentration in vacuo andpurification by silica gel chromatography (Hexane:EtOAc, 5:2) gave thetitle compound (1.5 g, 84%).

Step B

Following a similar procedure as that used in Preparative Example 13.29Steps C-G, except using the product from Step A above, the titlecompound was obtained (3%, MH⁺=380).

Preparative Examples 1312

Step A

Following a similar procedure as that used in Preparative Example 1311Step A, except using the commercially available sulfonylchloride, thediphenylsulfone was obtained (880 mg, 80%).

Step B

Following a similar procedure as that used in Preparative Example 11Step B, except using the product from Step A above, the title compoundwas obtained (0.90 g, 97%).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, except using the product from Step B above (0.16 g), the titlecompound was obtained (0.106 g, 95%).

Preparative Examples 1313

Step A

Following a similar procedure as that used in Preparative Example 1311Step A, except using the commercially available phenol (2 g), thenitroacid was obtained (˜13 mmol).

Step B

Oxallyl chloride (3.5 mL) and two drops of DMF was added to the productfrom Step A above (˜13 mmol) dissolved in dichloromethane (100 mL).After stirring at RT overnight, the mixture was concentrated in vacuo,diluted with dichloromethane (50 mL), cooled to 0° C. Dimethylamine inTHF (20 mL of 2N) and TEA (8 mL) were added. After 3 hr of stirring, themixture was concentrated in vacuo, aq NaOH (1M) was added, and themixture was extracted with dichloromethane. The pH of the aq layer wasadjusted to pH=2 using 6N HCl (aq), and extracted with dichloromethane.The combiuned organic extracts were washed with brine, dried,concentrated in vacuo, and the product purified by silica gelchromatography (700 mL dichloromethane/20 mL MeOH/1 mL AcOH) to give thetitle compound (800 mg, 27% for two steps).

Step C

Following a similar procedure as that used in Preparative Example 10.55Step C, except using the product from Step B above (780 mg), the titlecompound was obtained (0.46 g, 68%).

Preparative Examples 1313A

By following a similar procedure as that used in Preparative Example1001, steps C, D, E and F, using the known2-ethyl-6-methoxy-N,N-dimethyl-benzamide (WO 9105781, 2.1 g), the aminewas obtained (53%,1.1 g, MH⁺=209.1).

Preparative Examples 1313B

Step A

The benzamide (0.70 g, 3.125 mmol) was dissolved in dry ether (10 ml)under argon and cooled to −78 C. t-butyl lithium (4.2 mL, as 1.7Msolution in pentane) was added. The mixture was stirred at −78 C for 1.5hr. 2-Iodopropane (7.8 mmol) was added and the mixture warmed to roomtemperature and stirred for an additional 16 hrs. Water was added toquench, and the mixture was washed with water, then with 1N HCl. Theorganic phase was dried (Na2SO4) and concentrated. Flash columnchromatography (10:1 Hexane-EtOAC) provided the t-butyl compound (33 mg,4%, MH+=280.9).

Step B

A solution of the compound 1004 (1.2 g, 3.23 mmol) in dichloromethane(50 mL) was cooled to −75° C. 1M BBr₃ solution in dichloromethane (7.5mL, 7.5 mmol) was added dropwise with stirring. The mixture was stirredat −75° C. for 2 h. The mixture was added to ice-water. After stirringat rt for 0.5 h, the mixture was extracted with dichloromethane. Theorganic was concentrated and the residue was purified by columnchromatography (dichloromethane-methanol, 9:1 v/v) to give the product1005 as a yellow solid (1.05 g, 91%). m/e 357 (MH⁺), ¹H NMR (CDCl₃)δ8.44 (s, 1 H), 3.12 (s, 3 H), 2.87 (s, 3 H).

Preparative Example 1314

Step A

Methyl-4-bromo-3-hydroxy-2-thiophenecarboxylate (20 g, 84.36 mmol) wasdissolved in 400 mL of acetone. Potassium carbonate (58 g, 420.3 mmol)was added followed by iodomethane (45 mL, 424 mmol). The resultingmixture was heated at reflux for 4.5 h. After cooling, the mixture wasfiltered through a thin Celite pad, rinsing with methylene chloride. Thefiltrate was concentrated in vacuo to give 22.5 g ofmethyl-4-bromo-3-methoxy-2-thiophenecarboxylate (crude, 100%, MH⁺=251.0)as a dark green solid.

Step B

The product from Step A above (22.5 g, 84.36 mmol) was dissolved in 60mL of tetrahydrofuran and added with 125 mL of a 1.0M NaOH aqueoussolution. The mixture was stirred at room temperature for 4 d, thenwashed with ether (60 mL×2), acidified to pH ˜2 using a 1.0M HCl aqueoussolution. Solids were precipitated out after acidification, andcollected by filtration. The solid was dissolved in methylenechloride-ethyl acetate (˜4:1, v/v). The organic solution was washed withH₂O and brine, dried with Na₂SO₄, and concentrated in vacuo to a lightyellow solid, further dried on hight vacuum, yielding 17.95 g of4-bromo-3-methoxy-2-thiophene carboxylic acid (90%, MH⁺=237.0).

Step C

The carboxylic acid (3.26 g, 13.75 mmol) available from Step B above wastreated with 30 mL of concentrated sulfuric acid. The mixture was sealedin a one-neck round bottom flask, and heated at 65° C. for 4.5 h. Aftercooled to room temperature, the mixture was poured into 200 mL ofcrushed ice, and extracted with methylene chloride (100 mL×3). Theorganic extracts were combined, washed successively with H₂O (50 mL×2),sat. NaHCO₃ (50 mL×3), and brine (50 mL). The organic solution was driedwith Na₂SO₄, and concentrated in vacuo to a dark brown oil, which waspurified by flash column chromatography (biotage, SiO₂ column) usinghexanes-methylene chloride (3:1, v/v) as eluents. Removal ofsolvents-afforded 1.83 g of 3-bromo-4-methoxy thiophene (69%) as a lightyellow oil.

Step D

To a stirred solution of 3-bromo-4-methoxythiophene (550 mg, 2.85 mmol),prepared in Step C above, in 30 mL of methylene chloride at −78° C. wasadded dropwise along the inside wall of the flask chlorosulfonic acid(0.48 mL, 7.21 mmol). The mixture was stirred at −78° C. for 10 min,continued at room temperature for 1 h, and filtered through a 1-insilica gel pad, rinsing with methylene chloride. The filtrate wasconcentrated in vacuuo to give 270 mg of 4-bromo-3-methoxy-2-thiophenesulfonylchloride (33%) as a light yellow oil.

Step E

To a stirred solution of thiophene sulfonylchloride (270 mg, 0.926 mmol)prepared in Step D above in 15 mL of methylene chloride at roomtemperature was added triethylamine followed by N-methyl-tertbutylamine(0.25 mL, 2.094 mmol). After 20 h, the mixture was diluted with 50 mL ofmethylene chloride, and washed with H₂O and brine. The organic solutionwas dried over Na₂SO₄, filtered, and concentrated to an oily residue,which was purified by preparative TLC (methylene chloride as eluent) toafford 73 mg of the titled bromo-sulfonamide (23%) as a near colorlessoil.

Step F

A one-neck round bottom flask was charged with bromo-sulfonamide (73 mg,0.2133 mmol, from Step E above), palladium acetate (5 mg, 0.0223 mmol),binap (0.03212 mmol), cesium carbonate (139 mg, 0.4266 mmol), andbenzophenonimine (0.06 mL, 0.358 mmol). The mixture was evacuated viahouse vacuum, and refilled with nitrogen. A 3 mL of anhydrous toluenewas added. The mixture was evacuated again, refilled with nitrogen, andheated at reflux for 2.5 d. After cooled to room temperature, methylenechloride (50 mL) was added, the mixture was filtered through a Celitepad, rinsing with methylene chloride. The filtrated was concentrated invacuo to give 205 mg (crude, MH⁺=443.1) of the desired imine product asa dark brown oil, used in next step without purification.

Step G

The imine from Step F above (205 mg, crude, 0.2133 mmol) was dissolvedin 5 mL of methanol, and added with sodium acetate (81 mg, 0.9873 mmol)followed by hydroxylamine hydrochloride (68 mg, 0.98 mmol). The mixturewas stirred at room temperature for 6.5 h, quenched with the addition of10 mL of a 1.0M NaOH aqueous solution. The aqueous mixture was extractedwith methylene chloride (30 mL×3). The extracts were combined, washedwith brine, dried by Na₂SO₄, and concentrated in vacuo to a dark yellowoil, which was purified by preparative TLC (methylenechloride-methanol=100:1, v/v) to give 34 mg (57% over two steps,MH⁺=279.0) of methoxy-thiophenesulfonamide amine as a light yellow oil,solidified on standing.

Step H

To a stirred suspension of sodium hydride (60%, 45 mg, 1.13 mmol) in 3mL of anhydrous N,N′-dimethylformamide (DMF) was added dropwiseethanethiol (0.1 mL, 1.34 mmol). After 10 min, the mixture tured into aclear solution, and 1 mL of this solution was taken up in a syringe andadded dropwise to a stirred solution of methoxy-thiophenesulfonamideamine in 1 mL of DMF. The mixture was heated up to 95° C., and continuedfor 3.5 h. After cooling, the mixture was poured into 20 mL of a 1.0MNaOH aqueous solution. The aqueous mixture was washed with methylenechloride (30 mL×3). The organic washings were combined, re-extractedwith a 1.0M NaOH aqueous solution (15 mL) and H₂O (15 mL). The aqueouslayer and aqueous extracts were combined, adjusted to pH˜6 using a 1.0MHCl aqueous solution,and extracted with methylene chloride (75 mL×3).The organic extracts were washed with brine, dried (Na₂SO₄), andconcentrated in vacuo to a dark yellow oil. This oil was dissolved inethyl acetate (50 mL), washed with H₂O (10 mL×2) and brine (10 mL). Theorganic solution was dried (Na₂SO₄), and concentrated in vacuo to afford36 mg (100%, MH⁺=265.0) of hydroxyl-thiophene sulfonamide amine as ayellow oil.

Preparative Example 1315

Step A

Following the procedures described in Preparative Example 1314 Step E,4-bromo-3-methoxy-2-thiophene-sulfonyl chloride (190 mg, 0.65 mmol,available from Step D, Preparative Example 1314) was converted to thetitled tert-butyl sulfonamide (56 mg, 26%, MH⁺=328.1) upon treatment oftriethylamine (0.28 mL, 2.0 mmol) and tert-butylamine (0.15 mL, 1.43mmol) in 10 mL of methylene chloride.

Step B

tert-Butyl sulfonamide (98 mg, 0.3 mmol) available from Step A above wasconverted to the imine product (296 mg, crude, MH⁺=429.1) by using theprocedure described in Step F of Preparative Example 1314.

Step C

The imine product (296 mg, crude, ˜0.3 mmol) was transformed to thedesired thiophene-amine (23 mg, 30% over two steps, MH⁺=265.0) by usingthe procedure described in Step G of Preparative Example 1314.

Step D

If one were to apply the procedure set forth in Step H of PreparativeExample 1314, but using the thiophene amine available from Step C above,one would obtain the titled hydroxyl thiophene sulfonamide amine.

Preparative Expample 1316

Step A

Following the procedures set forth in Preparative example 13.29 Step Bthrough F, but using diethylamine, 3-methoxy-2-thiophenesulfonylchloride (available from Step A, Preparative example 13.29) wasconverted to titled diethylsulfonamido thiophene imine (MH⁺=429.1)

Step B

Thiophene-imine (1.5 g, 3.5 mmol), available from Step A above, wasdissolved in 30 mL of CH₂Cl₂, and added with potassium carbonate (1.2 g,8.70 mmol) followed by drop wise addition of bromine (0.32 mL, 6.25mmol). After stirred for 2 d, H₂O was added. The two layers wereseparated. The aqueous layer was extracted with CH₂Cl₂ (50 mL×2). Theorganic layers were combined, washed with a 10% Na₂S₂O₃ aqueous solution(40 mL×2). and brine (40 mL), dried over Na₂SO₄, and concentrated invacuo to a dark brown oil. This oil was separated by preparative TLC(CH₂Cl₂ as eluent), to give 0.96 g (54%) of the desired bromo-imine as abright yellow oil (M⁺=507,M+2=509)

Step C

Bromo-imine (0.95 g, 1.87 mmol), available from Step B above, wasdissolved in 15 mL of anhydrous THF, cooled in a −78° C. bath, andtreated with a 2.5M solution of n-butyl lithium in hexanes (1.2 mL, 3.0mmol) drop wise along the side wall of the flask. After 30 min,lodomethane (0.35 mL, 5.62 mmol) was added drop wise. Reaction wascontinued for 5 h, during which time the cooling bath was allowed towarm slowly to 0° C. The mixture was quenched by H₂O (25 mL), andextracted with CH₂Cl₂ (50 mL×2). The organic extracts were washed withbrine, dried with Na₂SO₄, and concentrated in vacuo to give 0.93 g(crude, >100%) of the desired methylated imine as a dark yellow oil(MH⁺=443.1)

Step D

The crude methyl-imine (0.93 g), prepared in step C above, was convertedto the methyl-hydroxyl-amine (0.21 g, 41%, MH⁺=265.0) by using theprocedures described in Step G of Preparative Example 13.29.

Preparative Example 1316A

Step A

Following the procedures described in Preparative Example 1314 Step E,but using cyclopropyl amine, the titled cyclopropyl-sulfonamide wasprepared from 4-bromo-3-methoxy-2-thiophene-sulfonylchloride (availablefrom Step D, Preparative Example 1314).

Step B

Cyclopropyl-sulfonamide, available from Step A above, was treated withpotassium carbonate and iodomethane in reflux acetone to affordN-methyl-N-cyclopropyl sulfonamide.

Step C, D, E

Following the procedures set forth in Preparative Example 1314, steps Fto H, N-methyl-N-cyclopropyl sulfonamide from Step B above was convertedto the hydroxyl-amino-thiophene sulfonamide (MH⁺=249.0)

Preparative Example 1317-1318

Following the procedures set forth in Preparative Example 1314 but usingthe commercially available amines, the hydroxyaminothiophene productslisted in the Table below could be prepared.

Prep. Ex. Amine Product 1317

1318

Example 1

To a stirred solution of the isothiazoledioxide from Preparative Example200 (30 mg, 0.078 mmol) and the p-toluene sulfonate salt of the aminefrom Preparative Example 75.1 (25 mg, 0.086 mmol; Note: pTSA saltprepared by combining 1 eq of pTSA and 1 eq of the amine from Prep. Ex.75.1 according to standard procedures) in ethanol (1 mL) was addeddiisopropyl ethyl amine (0.02 mL). The reaction mixture was stirred forfour hours at room temperature, solvents were removed under reducedpressure and purification by preparative silica gel TLC afforded theisothiazoledioxide ester product (26.9 mg, 68%, MH⁺=504.8).

Example 2

To a stirred solution of isothiazoledioxide from Preparative Example 200(30 mg, 0.078 mmol) and the p-toluene sulfonate salt of the amine fromPreparative Example 75.1 (25 mg, 0.086 mmol; Note: pTSA salt prepared bycombining 1 eq of pTSA and 1 eq of the amine from Prep. Ex. 75.1according to standard procedures) in ethanol (1 mL) was addeddiisopropyl ethyl amine (0.02 mL). The reaction mixture was stirred forfour hours at room temperature; solvents were removed under reducedpressure and stored under vacuum for one hour. The residue was treatedwith 1N NaOH at room temperature and the solution is heated at 60° C.for two hours. The reaction mixture was neutralized with 2N HCl (1 mL)and extracted with ethyl acetate (3×10 mL). The combined organic layerwas dried over anhydrous sodium sulfate, evaporation and purification bypreparative silical gel TLC (5% MeOH:CH₂Cl₂) gave the isothiazoledioxideproduct (7 mg, 8%, MH⁺=432.9).

Example 3

To a stirred solution of the isothiazoledioxide intermediate fromPreparative Example 201 (0.2 mmol) and the amine from PreparativeExample 3 (32 mg, 0.2 mmol) in ethanol (2 mL) was added diisopropylethyl amine (0.02 mL). The reaction mixture was stirred overnight atroom temperature, solvents were removed under reduced pressure andpurification by preparative silica gel TLC afforded theisothiazoledioxide ester product (4.7 mg, 5%, MH⁺=500.9).

Example 4

If one were to heat the product of Example 3 in a hydroxide solutionat >100° C. in a sealed tube for several hours, followed by subsequentacidification (2N HCl) of the mixture cooled to room temperature, theisothiazoledioxide product indicated could be obtained.

Example 5

Following a similar procedure as that described in Example 1, exceptusing the amine from Preparative Example 75.61, the isothiazoledioxideester product was obtained (43.5 mg, 51%, MH⁺=532.7).

Example 6

The product from Example 5 (40 mg, 0.075 mmol) was treated with 1N NaOHand stirred and heated at 60° C. for three hours. The reaction mixturewas neutralized with 2N HCl (1 mL) and extracted with ethyl acetate(3×10 mL). The combined organic layer was dried over anhydrous sodiumsulfate, evaporation and purification by preparative silical gel TLC(CH₂Cl₂) gave the isothiazoledioxide product (7.5 mg, 22%, MH⁺=460.8).

Examples 100-119, 121-124, 129 and 130

If one were to follow a procedure similar to that set forth in Examples5 and 6, but using the amines and the isothiazoledioxide intermediatesfrom the Preparative Examples indicated in the Table below, theisothiazoledioxide products could be obtained.

Prep Ex of isothiazole- dioxide Prep Ex Ex. intermediate (Amine) Product100 300 75.9

101 300 75.44

102 300 75.1

103 300 75.61

104 301 75.9

105 301 75.44

106 301 75.1

107 301 75.61

108 302 75.1

109 302 75.61

110 302 75.9

111 302 75.44

112 303 75.1

113 303 75.9

114 303 75.61

115 303 75.44

116 304 75.1

117 304 75.9

118 304 75.61

119 304 75.44

121 305 75.1

122 305 75.9

123 305 75.61

124 305 75.44

129 303 1048

130 303 603E

Examples 131-150, 152-155, 160 and 161

If one were to follow a procedure similar to that set forth in Examples3 and 4, but using the amines and the isothiazoledioxide intermediatesfrom the Preparative Examples indicated in the Table below, theisothiazoledioxide products could be obtained.

Prep Ex of isothiazole- dioxide Prep Ex Ex. intermediate (Amine) Product131 307 3

132 308 3

133 309 3

134 310 3

135 307 1001

136 308 1001

137 309 1001

138 310 1001

139 309 19

140 310 19

141 307 19

142 308 19

143 309 13.32A

144 307 13.32A

145 310 13.32A

146 308 13.32A

147 309 1316

148 307 1316

149 310 1316

150 308 1316

152 309 1316A

153 307 1316A

154 310 1316A

155 308 1316A

160 311 13.32A

161 312 13.32A

Examples 162-181, 183-186, 191-213, 214-217, 222-263

Following a procedure similar to that set forth in Example 5, but usingthe amine and the isothiazoledioxide intermediate from the PreparativeExample indicated in the Table below, the isothiazoledioxide product ofExample 162 was obtained.

If one were to follow a procedure similar to that set forth in Example5, but using the amines and the isothiazoledioxide intermediates fromthe Preparative Examples indicated in the Table below, theisothiazoledioxide products of Examples 163-181, 183-186, 191-213,214-217, 222-263 could be obtained.

Ex. Prep Ex of isothiazole-dioxide intermediate Prep Ex (Amine) Product162 300 75.9

163 300 75.44

164 300 75.1

165 XXX 75.61

166 301 75.9

167 301 75.44

168 301 75.1

169 301 75.61

170 302 75.1

171 302 75.61

172 302 75.9

173 302 75.44

174 303 75.1

175 303 75.9

176 303 75.61

177 303 75.44

178 304 75.1

179 304 75.9

180 304 75.61

181 304 75.44

183 305 75.1

184 305 75.9

185 305 75.61

186 305 75.44

191 303 1048

192 303 603E

193 307 3

194 308 3

195 309 3

196 310 3

197 307 1001

198 308 1001

199 309 1001

200 310 1001

201 309 19

202 310 19

203 307 19

204 308 19

205 309 13.32A

206 307 13.32A

207 310 13.32A

208 308 13.32A

209 309 1316

210 307 1316

211 310 1316

212 308 1316

214 309 1316A

215 307 1316A

216 310 1316A

217 308 1316A

222 311 13.32A

223 312 13.32A

224 350 75.1

225 350 75.9

226 350 75.61

227 351 75.1

228 351 75.9

229 351 75.61

230 352 75.1

231 352 75.9

232 352 75.61

233 353 3

234 354 75.1

235 354 75.9

236 354 75.61

237 355 75.1

238 355 75.9

239 355 75.61

240 356 75.1

241 356 75.9

242 356 75.61

243 357 3

244 358 75.1

245 358 75.9

246 358 75.61

247 359 75.1

248 359 75.9

249 359 75.61

250 360 75.1

251 360 75.9

252 360 75.61

253 361 3

254 362 75.1

255 362 75.9

256 362 75.61

257 363 75.1

258 363 75.9

259 363 75.61

260 364 75.1

261 364 75.9

262 364 75.61

263 365 3

Examples of disease-modifying antirheumatic drugs include, for example,methotrexate, sulfasalzine, leflunomide, TNFα directed agents (e.g.,infliximab, etanercept, and adalimumab), IL-1 directed agents (e.g.,anakinra) B cell directed agents (e.g., rituximab), T cell directedagents (e.g., alefacept, efalizumab, and CTLA4-Ig), TNFα-convertingenzyme inhibitors, interleukin-1 converting enzyme inhibitors, and p38kinase inhibitors.

The term “other classes of compounds indicated for the treatment ofrheumatoid arthritis”, as used herein, unless indicated otherwise,means: compounds selected from the group consisting of: IL-1 directedagents (e.g., anakinra); B cell directed agents (e.g., rituximab); Tcell directed agents (e.g., alefacept, efalizumab, and CTLA4-Ig),TNFα-converting enzyme inhibitors, interleukin-1 converting enzymeinhibitors, and p38 kinase inhibitors.

Angina is a CXCR2 mediated disease treatable with the CXCR2 antagonistcompounds of this invention. Thus, another embodiment of this inventionis directed to a method of treating angina in a patient in need of suchtreatment comprising administering to said patient a therapeuticallyeffective amount of a compound (a CXCR2 antagonist compound) of formulaIA.

While the present invention has been described in conjunction withspecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound of the formula:

or a pharmaceutically acceptable salts thereof, wherein: D and E areindependently selected from the group consisting of: N and CR⁵⁰,provided that D and E are not the same; R⁵⁰ is selected from the groupconsisting of: H, —C(O)R¹³, —C(O)OR¹³, —C(O)NR¹³R¹⁴, —S(O)₂NR¹³R¹⁴,—CF₃, —CN, —NO₂, —NR¹³R¹⁴, R¹³ and halo; A is selected from the groupconsisting of:

 wherein the A (2) group is substituted with at least one alkyl group; Bis

R² is OH; R³ is —C(O)NR¹³ ¹⁴; R₄ is hydrogen; R₅ and R⁶ are hydrogen;each R⁷ and R⁸ is independently selected from the group consisting of:H, and unsubstituted alkyl and; each R¹³ and R¹⁴ is independentlyselected from the group consisting of: H, and unsubstituted alkyl. 2.The compound of claim 1 wherein substituent A is unsubstituted orsubstituted with 1 or 2 alkyl groups wherein each alkyl group isindependently selected, R⁷ is alkyl and R⁸ is H.
 3. The compound ofclaim 1 wherein substituent A is substituted with 1 or 2 alkyl groupsindependently selected from the group consisting of methyl, ethyl andisopropyl, R⁷ is selected from the group consisting of: ethyl, isopropyland t-butyl, and R⁸ is H.
 4. The compound of claim 1 wherein A isselected from the group consisting of:


5. The compound of claim 1 wherein A is selected from the groupconsisting of:


6. The compound of claim 1 wherein substituent A is selected from thegroup consisting of:


7. The compound of claim 1 wherein B is:


8. The compound of claim 1 wherein said compound of formula IA is acompound of formula IA.1:

or a pharmaceutically acceptable salt thereof.
 9. The compound of claim1 wherein said compound of formula IA is a compound of formula IA.2:

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 wherein R⁵⁰ is H.
 11. The compound of claim 1 wherein R⁵⁰ is —C(O)R¹³.12. The compound of claim 1 wherein R⁵⁰ is —C(O)OR¹³.
 13. The compoundof claim 1 wherein R⁵⁰ is —C(O)NR¹³R¹⁴.
 14. The compound of claim 1wherein R⁵⁰ is —S(O)₂NR¹³R¹⁴.
 15. The compound of claim 1 wherein R⁵⁰ is—CF₃.
 16. The compound of claim 1 wherein R⁵⁰ is —CN.
 17. The compoundof claim 1 wherein R⁵⁰ is —NO₂.
 18. The compound of claim 1 wherein R⁵⁰is —NR¹³R¹⁴.
 19. The compound of claim 1 wherein R⁵⁰ is halo.
 20. Thecompound of claim 1 wherein substituent A in formula IA isunsubstituted, or substituted with 1 to 3 substituents independentlyselected from the group consisting of: alkyl; R⁷ is selected from thegroup consisting of: H, methyl, ethyl, isopropyl, and t-butyl; and R⁸ isH.
 21. The compound of claim 1 wherein: substituent A in formula IA isselected from the group consisting of:

R¹³ and R¹⁴ are independently selected from the group consisting of Hand methyl.
 22. The compound of claim 1 wherein substituent A isselected from the group consisting of:

and substituent B is:


23. A pharmaceutically acceptable salt of a compound of claim
 1. 24. Asodium salt of a compound of claim
 1. 25. A calcium salt of a compoundof claim
 1. 26. The compound of claim 1 selected from the groupconsisting of

and the pharmaceutically acceptable salts thereof.
 27. The compound ofclaim 1 selected from the group consisting of

and the pharmaceutically acceptable salts thereof.
 28. The compound ofclaim 1 selected from the group consisting of

and the pharmaceutically acceptable salts thereof.
 29. The compound ofclaim 1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 30. The compound of claim1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 31. The compound of claim1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 32. The compound of claim1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 33. The compound of claim1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 34. The compound of claim1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 35. The compound of claim1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 36. The compound of claim1 wherein said compound is

or a pharmaceutically acceptable salt thereof.
 37. The compound of claim1 in isolated and pure form.
 38. A pharmaceutical composition comprisingat least one compound of claim 1, or a pharmaceutically acceptable saltthereof, in combination with a pharmaceutically acceptable carrier. 39.A pharmaceutical composition comprising at least one compound of claim1, or a pharmaceutically acceptable salt thereof, and at least one otheragent, medicament, antibody and/or inhibitor for treating a chemokinemediated disease, in combination with a pharmaceutically acceptablecarrier.